7,11-methanocycloocta [B] quinoline derivative as highly functionalizable acetylcholinesterase inhibitors

ABSTRACT

New highly functionalizable Huprine derivatives of formula I: 
                         
and
     a method for preparing such compounds and their use for treating neurological diseases in which the level of acetylcholine is affected such as Alzheimer&#39;s disease.

The present invention concerns new highly functionalizable Huprinederivatives and a method for preparing such compounds. Huprinederivatives are acetylcholinesterase inhibitors and, for this reason,are promising candidates for treating neurological diseases in which thelevel of acetylcholine is affected such as Alzheimer's disease.

Alzheimer's disease is nowadays a main public health subject havingeconomic and human impact which is intended to grow with the ageing ofthe population. Among the different solutions investigated for treatingneurodegenerative diseases, and especially Alzheimer's disease, the onlytreatment resulting in efficient compounds which are currentlycommercialized is a symptomatic treatment of the cholinergicdeficiencies: acetylcholinesterase (AchE), the key enzyme ending theprocess of nerve impulse transmission, is inhibited by continuouslyadministrating reversible acetylcholinesterase inhibitors. Currently,the four compounds approved by international regulatory organizationsregarding public health are Tacrine (Cognex®), Donepezil (E2020,Aricept®), Rivastigmine (Exlon®) and Galanthamine (Reminyl®). However,those compounds and their derivatives have low liposolubility and thusdo not easily cross the blood-brain barrier. Furthermore, besides thefact that the treatment is assumed to be a life-time treatment and thatit involves non negligible side effects, those compounds do not exhibita sufficiently high affinity to the AChE. Therefore, the need remain foralternative new compounds having a higher efficiency than Donepezilwhich is the reference among currently commercialized and able to crossthe blood-brain barrier. Moreover, prodrugs delivering the activecompound only when the target is reached, would allow decreasing thetoxicity of such life-time treatment.

At the end of the 90s, Camps et al. discovered new hybrid compounds ofTacrine and Huperzine, named Huprines, which are the most efficientmonomeric inhibitors of AChE currently known (Huprines X and Y have anIC₅₀ around 1 nM). However, those compounds still exhibit renderinghepatic toxicity and decreasing the effective amount needed for thetreatment is essential. The Huprines derivatives described in WO97/13754 present some possibilities for structural arrangement but thefunctionalization of those compounds is limited. Therefore, the need ofhighly functionalizable Huprine derivatives remains to adapt the desiredpharmacologic properties.

The inventors have now found a new process for preparing Huprinederivatives. This process is fast, efficient and allows introducing anester function on position 9 which is easily modified into variousfunctions through additional reaction steps.

In the present invention, the term “pharmaceutically acceptable salts”refer to salts which are not deleterious to the patient and compatiblewith a use in a pharmaceutical composition. Pharmaceutically acceptablesalts of the compounds of the invention include the acid addition andbase salts thereof. Suitable acid addition salts are formed from acidswhich form non-toxic salts. Examples include the acetate, adipate,aspartate, benzoate, besylate, bicarbonate/carbonate,bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate,esylate, formate, fumarate, gluceptate, gluconate, glucuronate,hexafluorophosphate, hibenzate, hydrochloride/chloride,hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate,maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate,nicotinate, nitrate, orotate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate,saccharate, stearate, succinate, tannate, tartrate, tosylate,trifluoroacetate and xinofoate salts. Suitable base salts are formedfrom bases which form non-toxic salts. Examples include the aluminium,arginine, benzathine, calcium, choline, diethylamine, diolamine,glycine, lysine, magnesium, meglumine, olamine, potassium, sodium,tromethamine, 2-(diethylamino)ethanol, ethanolamine, morpholine,4-(2-hydroxyethyl)morpholine and zinc salts. Hemisalts of acids andbases may also be formed, for example, hemisulphate and hemicalciumsalts. Preferred, pharmaceutically acceptable salts includehydrochloride/chloride, hydrobromide/bromide, bisulphate/sulphate,nitrate, citrate, and acetate.

In the present invention, the term “prodrug” refers to any compoundwhich is a metabolic precursor of the compounds of the invention. Itincludes any compound transformable to deliver an effective amount of apharmaceutically active compound of the invention said transformationcan be chemical, enzymatic or any other transformation resulting in thein vivo delivery of the compound of the invention. A prodrug can be aninactive compound when administrated to the patient. The prodrugs of thecompounds of the invention can be easily determined by the skilledperson in the art.

In the present invention the term “neurological condition” refers to agroup of disorders that involve any part of the nervous system resultingfrom damage to the brain, spinal column or nervous system caused byillness or injury. In particular, neurological conditions includeAlzheimer's disease, multiple sclerosis, cognitive disorders, memorydisorder, depressive disorders, bipolar disorder and schizophrenicdisorders, Parkinson's’ disease, Huntington's disease, vasculardementia, fronto-temporal dementia, Lewy bodies dementia,Creutzfeld-Jacob disease, epilepsy, migraine, anxiety, panic, psychosis,hypersensitive syndrome or pain.

The present invention thus concerns highly functionalizable Huprinederivatives of formula I:

wherein,

R is a moiety comprising at least one functional group selected from thegroup consisting of a double bond, halo, cyano, hydroxyl, sulfonyl,aldehyde, carbonyl, carboxyl, ether, ester, carboxamide, amine,hydrazinyl, ammonium, azide and 5- or 6-membered heterocyclic group withthe proviso that R is not allyl;

R^(a), R^(b), R^(c) and R^(d) are independently H, halogen, cyano,carboxyl, —O(C₁-C₄ alkyl), —S(C₁-C₄ alkyl), or —CH₂S(C₁-C₄ alkyl);preferably H, halogen, cyano, —SCH₃ or —CH₂SCH₃; more preferably H orCl; even more preferably R^(a), R^(b) and R^(d) are H and R^(c) is H orCl;

R¹ is H or ═CH₂; and

R² is C¹ or NR³R′³ wherein R³ and R′³ are independently H, acetyl, C₁-C₄alkyl, —CO(C₁-C₄ alkyl) or any hydrocarbyl chain linked to a ligand ofthe peripheral site of the AChE, preferably selected fromphenyltetraisoquinoline derivatives, beta-carboline derivatives, indolederivatives or coumarine derivatives; preferably, R³ and R′³ areindependently H, acetyl, C₁-C₄ alkyl or —CO(C₁-C₄ alkyl); morepreferably, R³ and R′³ are independently H or acetyl.

Preferably, R is a moiety of formula:-A-Y—Zwherein,

A is C₁-C₄ alkylene or C₂-C₄ alkenylene; in a preferred embodiment, A isa linear C₁-C₄ alkylene or a linear C₂-C₄ alkenylene; more preferably, Ais a linear C₁-C₄ alkylene or —CH═CH—; in another preferred embodiment,A is a branched C₁-C₄ alkylene or a branched C₂-C₄ alkenylene;

Y is a single bond, —O—, —C(O)—, —C(O)O—, —OC(O)—, —OS(O)₂—, —NH—,—N(R⁴)— or

Z is H, halo, cyano, hydroxyl, azide, hydrazinyl, —OR⁵, —C(O)OR⁶,—NR⁶R⁷, —N⁺R⁶R⁷R⁸, —CH(COOR⁶)₂, —CH(CH₂OH)₂, CH₂—OC(O)—R⁹, C₁-C₄ alkyl,C₁-C₄ alkyl substituted with halogen or hydroxyl, C₂-C₄ alkenyl or C₂-C₄alkenyl substituted with halogen or hydroxyl; preferably Z is H, halo,cyano, hydroxyl, azide, hydrazinyl, —OR⁵, —C(O)OR⁶, —NR⁶R⁷, —N⁺R⁶R⁷R⁸,—CH(COOR⁶)₂, —CH(CH₂OH)₂, CH₂—OC(O)—R⁹, methyl, ethyl, ethenyl,hydroxymethyl or trifluoromethyl;

R⁴ and R⁵ are independently C₁-C₄ alkyl or C₁-C₄ alkyloxycarbonyl;preferably, R⁴ and R⁵ are independently methyl or butyloxycarbonyl;

R⁶, R⁷ and R⁸ are independently H or C₁-C₄ alkyl; preferably, R⁶, R⁷ andR⁸ are independently H, methyl or ethyl; and

R⁹ is C₁-C₄ alkyl or C₁-C₄ alkyl substituted with halogen; preferably,R⁹ is methyl or trifluoromethyl;

with the proviso that R is not alkyl or allyl.

More preferably, R is selected from the group consisting of—CH₂—COO—C₂H₅, —(CH₂)₂—OH, —CH═CH₂, —(CH₂)₂—OCO—CH₃, —(CH₂)₂—OCO—CF₃,—(CH₂)₂—O—CH₃, —(CH₂)₂—I, —(CH₂)₂—CN, —(CH₂)₂—Cl, —(CH₂)₂—F, —CH₂—COOH,—(CH₂)₂—N₃, —(CH₂)₂—OSO₂—CH₃, —(CH₂)₂—NH—NH₂, —(CH₂)₂—NH—OH,—(CH₂)₂—N(boc)-O(boc), —(CH₂)₂—OCO—NH₂, —(CH₂)₂—OCO—CH═CH₂,—CH₂—CO—N(CH₃)₂, —CH₂—CONH₂, —(CH₂)₂—N⁺H(CH₃)₂, —(CH₂)₂—(C₂H₂N₃)—COOCH₃,—(CH₂)₂—(C₂H₂N3)—CH₂OH, —(CH₂)₂—N⁺H₃, —(CH₂)₂—N⁺(CH₃)₃,—(CH₂)₂—CH—(COOCH₃)₂, —(CH₂)₂—CH—(COOC₂H₅)₂, —(CH₂)₂—CH—(CH₂OH)₂,—(CH₂)₃—COO—CH3, —(CH₂)₄—OH, —(CH₂)₄—OSO₂—CH₃, —(CH₂)₄—N₃,—(CH₂)₄—(C₂H₂N₃)—COOCH₃, —(CH₂)₄—(C₂H₂N₃)—CH₂OH,—(CH₂)₄—(C₂H₂N₃)—CH₂OCOCF₃, —(CH₂)₃—COO—C₂H₅.

The invention also concerns the pharmaceutically acceptable salts andprodrugs of compounds of formula I.

The expression “C₁-C₄ alkyl” represents any monovalent radical of alinear or branched hydrocarbon chain comprising 1 to 4 carbon atom suchas methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl ort-butyl.

The expression “C₂-C₄ alkenyl” represents any monovalent radical of alinear or branched hydrocarbon chain comprising 2 to 4 carbon atom andat least one double bond, such as ethenyl, n-propenyl, i-propenyl,n-butenyl, i-butenyl, s-butenyl or t-butenyl.

The expressions “C₁-C₄ alkyl substituted with halogen or hydroxyl” or“C₂-C₄ alkenyl substituted with halogen or hydroxyl” represent any C₁-C₄alkyl or C₂-C₄ alkenyl group substituted with at least one halogen atom(selected from F, Cl or Br) or at least one hydroxyl group, such ashalomethyl, dihalomethyl, trihalomethyl, haloethyl, dihaloethyl,trihaloethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl orhydroxybutyl.

The expression “C₁-C₄ alkylene” represents any divalent radical of alinear or branched hydrocarbon chain comprising 1 to 4 carbon atom, suchas —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —CH(CH₃)—, —CH(CH₃)—CH₂—,—CH₂—CH(CH₃)—, —CH₂—CH₂—CH(CH₃)—, —CH₂—CH(CH₃)—CH₂— or—CH(CH₃)—CH₂—CH₂—.

The expression “C₂-C₄ alkenylene” represents any divalent radical of alinear or branched hydrocarbon chain comprising 2 to 4 carbon atom andat least one double bond, such as —CH═CH—, —CH═CH—CH₂—, —CH₂—CH═CH—,—CH═CH—CH₂—CH₂—, —CH₂—CH₂—CH═CH— or —CH₂—CH═CH—CH₂—.

The expression “5- or 6-membered heterocyclic group” represents 5- or6-membered saturated rings comprising at least one heteroatom selectedfrom N, O or S or unsaturated rings comprising at least one heteroatomselected from N, O or S and at least one double bond. Such heterocyclicgroup are for example pyrrolidine, pyrroline, pyrrole, imidazolidine,pyrazolidine, imidazole, imidazoline, pyrazole, pyrazoline, triazole,tetrazole, piperidine, pyridine, piperazine, diazine, triazine,tetrazine, tetrahydrofuran, dihydrofuran, dihydrofuran, furan,tetrahydropyran, pyran, dioxolane, dioxane, trioxane, dioxine,tetrahydrothiophene, dihydrothiophene, thiophene, dithiolane, thiane,dithiane or thiopyran.

The expression “5- or 6-membered heterocyclic group” represents 5- or6-membered saturated rings comprising at least one heteroatom selectedfrom N, O or S or unsaturated rings comprising at least one heteroatomselected from N, O or S and at least one double bound. Such heterocyclicgroup are for example pyrrolidine, pyrroline, pyrrole, imidazo lidine,pyrazo lidine, imidazole, imidazo line, pyrazole, pyrazo line, triazole,tetrazole, piperidine, pyridine, piperazine, diazine, triazine,tetrazine, tetrahydrofuran, dihydrofuran, dihydrofuran, furan,tetrahydropyran, pyran, dioxolane, dioxane, trioxane, dioxine,tetrahydrothiophene, dihydrothiophene, thiophene, dithio lane, thiane,dithiane or thiopyran.

The abbreviation “Me” represents a methyl group.

The abbreviation “Et” represents an ethyl group.

The abbreviation “Ac” represents an acetyl group.

The abbreviation “boc” represents a t-butyloxycarbonyl group.

In a first embodiment, the present invention concerns highlyfunctionalizable Huprine derivatives of formula Ia:

wherein R, R¹, R³, R′³, R^(a), R^(b), R^(c) and R^(d) are as defined informula I; preferably, R^(a), R^(b) and R^(d) are H and R, R¹, R³, R′³and R^(c) are as defined in formula I; and pharmaceutically acceptablesalts thereof.

In a first alternative of this embodiment, the present inventionconcerns highly functionalizable Huprine derivatives of formula Ia-1:

wherein R is as defined in formula I;and pharmaceutically acceptable salts thereof.

In a second alternative of this embodiment, the present inventionconcerns highly functionalizable Huprine derivatives of formula Ia-2:

wherein R is as defined in formula I; preferably, R is —(CH₂)₂—N₃,—(CH₂)₂—OSO₂—CH₃, —(CH₂)₂—N⁺H₃ or —(CH₂)₄—(C₂H₂N₃)—CH₂OH;and pharmaceutically acceptable salts thereof.

In a third alternative of this embodiment, the present inventionconcerns highly functionalizable Huprine derivatives of formula Ia-3:

wherein R is as defined in formula I; preferably, R is —CH₂—COO—C₂H₅,—(CH₂)₄—OH or —(CH₂)₄—(C₂H₂N₃)—CH₂OCOCF₃;and pharmaceutically acceptable salts thereof.

In a second embodiment, the present invention concerns highlyfunctionalizable Huprine derivatives of formula Ib:

wherein R, R¹, R³, R′³, R^(a), R^(b), R^(c) and R^(d) are as defined informula I; preferably, R^(a), R^(b) and R^(d) are H and R, R¹, R³, R′³and R^(c) are as defined in formula I;and pharmaceutically acceptable salts thereof.

In an alternative of this embodiment, the present invention concernshighly functionalizable Huprine derivatives of formula Ib-1:

wherein R is as defined in formula I; preferably, R is —CH₂—COO—C₂H₅;and pharmaceutically acceptable salts thereof.

In a particularly preferred embodiment, the compounds of the presentinvention are selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

This invention also relates to a method for preparing highlyfunctionalizable Huprine derivatives of formula I comprising the stepsof:

a) contacting the diketone of formula 1

with an α-haloester, to obtain the compound of formula 2

wherein R′ is a C₁-C₄ alkyl;b) transforming the alcoholic group of the compound of formula 2 into aleaving group to obtain the compound of formula 3

wherein R″ is a leaving group;b′) eventually converting the compound of formula 3 into the compound offormula 4

c) contacting the compound of formula 3 or 4 with the compound offormula 5

wherein R^(a), R^(b), R^(c) and R^(d) are as defined in formula I, andR^(e) is CN or COOH, to obtain the compound of formula HUP

wherein R′ is a C₁-C₄ alkyl and R¹⁰ is NH₂ or Cl.

The diketone of formula 1 is commercially available and is alsoobtainable from 1,1,3,3-tetramethoxypropane and methylacetone-1,3-dicarboxylate (Berz S. H., J. Org. Chem. 1985, 50, 3585).

The step a), introducing the functionalization, can be obtained by theaddition of an organometallic compound, such as zinc, magnesium orlithium derivative organometallic compounds, to the diketone offormula 1. Preferably, step a) is based on the reaction of Reformatskyby condensing the diketone of formula 1 with an α-haloester using zincmetal. The haloester is preferably a compound of formula X′CH2COOR′,wherein X′ is a halogen and R′ is a C1-C4 alkyl; more preferably, X′ isBr and R′ is a C1-C4 alkyl; even more preferably, X′ is Br and R′ ismethyl or ethyl. This reaction is preferably carried out in a polarsolvent; more preferably in tetrahydrofurane (THF) under reflux.

In step b), the alcoholic function of compound 2 is transformed into aleaving group. The leaving group R″ can be selected from Br, carbonate,an arylsulfonyloxy such as tosylate, an alkylsulfonyloxy such asmesylate, or a haloalkylsulfonyloxy such as triflate. This step isobtained by contacting the compound of formula 2 with an appropriatereactant well known by the skilled man, for example Br₂, anarylsulfonylhalide, an alkylsulfonylhalide or a haloalkylsulfonyloxy.The reactant is preferably selected from methylsulfonylchloride andp-toluenesulfonylchloride leading to compound 3 wherein R″ is mesylateor tosylate. The reaction condition can be easily determined by theskilled person. Preferably, step b) is carried out in a polar aproticsolvent, for example dichloromethane, in presence of a base, such astriethylamine, at 0° C.

The conversion of the compound 3 into compound 4 in step b′) can be madeby using a silica gel in an apolar aprotic solvent, such as1,2-dichloroethane, under reflux. This conversion is however preferablyobtained more quickly and with a higher yield in an apolar aproticsolvent, such as 1,2-dichloroethane, under reflux in the presence of aLewis acid, for example aluminium trichloride.

The condensation of compound 3 or 4 with the compound 5 in step c) iscarried out by following the Friedländer reaction. This reaction is madein apolar aprotic solvent, preferably 1,2-dichloroethane, under refluxin presence of a Lewis acid, such as aluminium trichloride. Whencompound 5 is chosen among aminobenzonitril derivatives (i.e. when R^(e)is CN), step c) leads to the compound of formula (HUP) wherein R¹⁰ isNH₂. Preferred aminobenzonitril derivatives are 2-aminobenzonitrile(R^(e) is CN, and R^(a), R^(b), R^(c) and R^(d) are H) or4-chloro-2-aminobenzonitrile (R^(e) is CN, R^(a), R^(b) and R^(d) are Hand R^(c) is Cl). When the compound of formula 5 is chosen amongaminobenzoic acid derivatives (i.e. when R^(e) is COOH), a furtherreaction in presence of phosphorous oxychloride leads to the compound offormula (HUP) wherein R¹⁰ is Cl. Preferred aminobenzoic acid derivativesare are 2-aminobenzoic acid (R^(e) is COOH, and R^(a), R^(b), R^(c) andR^(d) are H) or 4-chloro-2-aminobenzoic acid (R^(e) is COOH, R^(a),R^(b) and R^(d) are H and R^(c) is Cl).

In a first embodiment, the method of the invention comprises the stepsof:

a) contacting the diketone of formula 1

with an α-haloester, to obtain the compound of formula 2

wherein R′ is a C₁-C₄ alkyl;b) transforming the alcoholic group of the compound of formula 2 into aleaving group to obtain the compound of formula 3

wherein R″ is a leaving group;b′) converting the compound of formula 3 into the compound of formula 4

c) contacting the compound of formula 4 with the compound of formula 5

wherein R^(a), R^(b), R^(c) and R^(d) are as defined in formula I, andR^(e) is CN or COOH, to obtain the compound of formula HUP

wherein R′ is a C₁-C₄ alkyl and R¹⁰ is NH₂ or Cl.

In a second embodiment, the method of the invention comprises the stepsof:

a) contacting the diketone of formula 1

with an α-haloester, to obtain the compound of formula 2

wherein R′ is a C₁-C₄ alkyl;b) transforming the alcoholic group of the compound of formula 2 into aleaving group to obtain the compound of formula 3

wherein R″ is a leaving group;c) contacting the compound of formula 3 with the compound of formula 5

wherein R^(a), R^(b), R^(c) and R^(d) are as defined in formula I, andR^(e) is CN or COOH, to obtain the compound of formula HUP

wherein R′ is a C₁-C₄ alkyl and R¹⁰ is NH₂ or Cl.

The advantage of this embodiment is that compound 3 is directlytransformed into the compound HUP in a one-potfragmentation-Friedländer's condensation reaction carried out in stepc).

The compounds of formula I can be obtained from the compound of formulaHUP through further additional steps which are easily determined by theskilled person in the art for rearranging the functionalization onposition 9. Some of the possible functional rearrangments are detailedin the following examples.

The compounds of the invention exhibit high affinity towards the AChEand the BuChE (butyrylcholinesterase), with a high specificity towardAChE when a chlorine atome si substitutes on position 3 of the compoundsof the invention. Moreover, such compounds are accessible via relativelysimple synthesis allowing a high adaptability of their molecularstructure, especially on position 9. Consequently, the compounds of theinvention can be use in various applications exploiting their highaffinity toward the AChE and the BuChE and their highfunctionalizability. Among possible applications, the compounds of theinvention can be used, for example, as an inhibitor of the AChE or theBuChE, especially for treating neurodegenerative diseases or for thestructural analysis of the complex AChE-inhibitor; as probes for theevolution of neurodegenerative disease through mapping of the functionalcholinergic neurons; taking into account their high selectivity towardsAChE or BuChE, as selector or chiral selector for affinitychromatography and purification of those enzymes; or, taking intoaccount their particular structures, as enantioselective catalyst.

Due to their high affinity towards the AChE and the BuChE, the compoundsof the invention can be used as inhibitors of the AChE or the BuChE. Thepresent invention also concerns an inhibitor or part of an inhibitor ofthe AChE or the BuChE of general formula I. It also concerns the use ofa compound of formula I as an inhibitor of the AChE or the BuChE.

Several inhibitor of the AChE, as disclosed above, are alreadyavailable. However, although many compounds exhibit high affinity invitro, only few compounds can be used as active principle because thosecompounds and their derivatives risk having a low liposolubility andthus do not cross easily the blood-brain barrier. On the contrary, inaddition to the nanomolar affinity and the high selectivity of thecompounds of the invention for the AChE, lipophilic vector can be easilycoupled to the compounds of the invention. The high functionalizabilityof the compounds of the invention can be used to mask the hydrophilicproperties of the inhibitor thanks to an enzymolabil function or afunction labil under particular conditions such as redox chemicaldelivery systems based on NADH models developed by Bodor et al. (Eur. J.Med. Chem. Volume 39, Issue 8, 2004, Pages 715-727). It is thus possibleto produce a highly lipophilic pharmaceutically inactive prodrug of aninhibition of the AChE allowing the inhibitor to cross the blood-brainbarrier. Once inside the central nervous system, the prodrug istransformed into the hydrosoluble active form which is trapped insidethe blood-brain barrier. The availability of the active compound towardsthe target is then increased and the effective dose can be reduced.Consequently, the side effects and peripheral effects induced by thosecompounds are minimized. For example, the hydrosoluble compound (HUP 2),having an activity as high as the Huprine X, comprises an alcoholfunction which can be coupled into a lipophilic vector such as acetate(HUP 4) or trifluoroacetate (HUP 5). A gain up to 1.5 units for the logP is obtained compared to the Huprine X. More generally, long chainfatty acid esters or other lipophilic substituent can be branched on theadequately functinalized position 9 allowing adapting the lipophilicproperties of the compound.

The present invention also concerns dimeric compounds consisting of thecompound of formula I further coupled to another molecular structure.Since any desired function can be branched on the position 9, thecompound of the invention can be further coupled to another molecularstructure so as to form a dimeric compound. Therefore, the compound offormula I is advantageously coupled to said molecular structure throughan appropriate functionalization on position 9. The molecular structurecoupled to the compound of formula I is chosen among compounds havingtheir own activity so as to confer specific properties to the dimericcompound, e.g. enhanced inhibiting properties or additional propertiessuch as a role in the aggregation of beta-amyloid peptids. Saidmolecular structure is for example selected from phenyltetraisoquinolinederivatives, beta-carboline derivatives, indole derivatives or coumarinederivatives.

Alzheimer disease is the most prevalent type of senile dementia. Theinvariable histological hallmark of the disease is the deposition in thebrain tissue of amyloid plaques, whose main constituent is a 40-42amino-acids peptide referred to the amyloid-beta peptide. Thebeta-amyloid peptide forms oligomeric and fibrillar assemblies that haveboth been shown to be toxic. Accumulating evidence from in vitro studiessuggest that toxicity is greater for oligomers compared to fibrils.

In addition to the plaques, a decrease in acetylcholine levels isobserved in the brains of Alzheimer disease patients. Therefore,symptomatic treatment has focused so far on AChE reversible inhibition.This is illustrated by the fact that four out of the five currentlyapproved Alzheimer disease drugs targeted the AChE active site. It hasbeen shown that beta-amyloid peptide interacts with AChE following amechanism involving its peripheral site and residues 12-28 of thebeta-amyloid peptide. This interaction results in the acceleration ofbeta-amyloid peptide/fibrils deposition and an increase ofamyloid-plaques neurotoxicity. Second-generation anti-Alzheimer diseasedrugs are therefore intended to exert their action by targeting both theperipheral and the active site of AChE, thereby restoring brainacetylcholine levels, on one hand, and inhibiting AChE-mediatedacceleration of amyloid-beta peptide fibrillation, on the other hand. Inthis context, dimeric compounds consisiting of the compound of formula Icoupled to a ligand of AChE peripheral site have been designed. Thehuprine moiety tightly binds to AChE active site, while the ligand ofthe peripheral site is anchored at the peripheral site. Accordingly,such dimeric compounds, such as HUP32-COU1, are very potent inhibitorsof AChE that feature a dissociation constant in the picomolar-range.

Among such dimeric compounds, dimeric inhibitors are particularlyinteresting. Indeed, the AChE presents two active sites, an acylationsite and a peripheral site, connected through an internal gorge. Thecompounds of formula I have a high affinity towards the acylation site.In a particular embodiment, the present invention concerns a dimericcompound consisiting of the compound of formula I further coupled to aligand of the peripheral site of the AChE or the BuChE. The length ofthe substituent of the 9 position of the Huprine of formula I can beadapted so that the dimeric inhibitor presents an adapted structure toinhibit at the same time the two active sites of the AChE.Noteworthingly, all such dimeric inhibitors have been designed to datethrough modification of the aniline function at the position 12 ofHuprines and Tacrines. Yet, providing an X-ray crystallographicstructure of derivative (HUP2) in the acylation site of human AChEallowed us to discover that the 9 position offered a more flexibleaccess to the peripheral site of AChE. The coupling of the Huprines offormula I and the ligand of the peripheral site can for example beperformed with a Huisgen 1,3-dipolar cyloaddition. The compounds offormula I are preferably coupled to a ligand of the peripheral site ofthe AChE selected from phenyltetraisoquinoline derivatives,beta-carboline derivatives, indolic derivatives and coumarinderivatives. More preferably, the dimeric inhibitor is selected fromcompounds of formula HUP32-PIQ1, HUP32-PIQ2, HUP32-PIQ3, HUP32-PIQ4,HUP32-COU1, HUP32-COU2, HUP32-COU3, HUP32-IND1, HUP32-IND2, HUP32-TPI1,HUP32-TPI2, HUP32-PPI1 and HUP32-PPI2:

The present invention also concerns a dimeric inhibitor of the AChE orthe BuChE seleted form dimeric compounds consisting of the compound offormula I further coupled to a ligand of the peripheral site of theacetylcholinesterase or the butyrylcholinesterase, preferably selectedfrom phenyltetraisoquinoline derivatives, beta-carboline derivatives,indolic derivatives and coumarin derivatives, more preferably selectedfrom compounds of formula HUP32-PIQ1, HUP32-PIQ2, HUP32-PIQ3,HUP32-PIQ4, HUP32-COU1, HUP32-COU2, HUP32-COU3, HUP32-IND1, HUP32-IND2,HUP32-TPI1, HUP32-TPI2, HUP32-PPI1 and HUP32-PPI2. The present inventionalso concerns the use of such dimric compounds as a dimeric inhibitor ofthe AChE or the BuChE. The dimeric inhibitors have an increased affinitytowards the AChE compared to the compounds of formula I. Also, thedimeric compounds can have a role upstream from neurodegenerativediseases through the prevention of β-amyloid plaques deposit responsiblefor such diseases.

AChE inhibitors inhibit the cholinesterase enzyme from breaking downacetylcholine, increasing both the level and duration of action of theneurotransmitter acetylcholine. The compounds of formula I are thereforeuseful for treating neurological conditions where cholinergicdeficiencies are involved. An object of the invention is therefore thecompound of formula I, the inhibitor of formula I or the dimericinhibitor as defined above for the manufacture of a medicament.Especially, the present invention also concerns the compound of formulaI, the inhibitor of formula I or the dimeric inhibitor as defined abovefor the manufacture of a medicament for the treatment, preferably thepalliative treatment, of neurological condition.

The invention is also dedicated to the use of a the compound of formulaI, the inhibitor of formula I or the dimeric inhibitor as defined abovefor the manufacture of a medicament, preferably a medicament for thetreatment of neurological condition, more preferably, the palliativetreatment of neurological condition.

The invention also concerns the compound of formula I or the dimericcompound as defined above for use in the therapeutical treatment of thehuman body, preferably in the treatment or prevention of a neurologicalcondition.

The neurological condition is preferably selected from the groupconsisting of Alzheimer's disease, multiple sclerosis, cognitivedisorders, memory disorder, depressive disorders, bipolar disorder andschizophrenic disorders, Parkinson's’ disease, Huntington's disease,vascular dementia, fronto-temporal dementia, Lewy bodies dementia,Creutzfeld-Jacob disease, epilepsy, migraine, anxiety, panic, psychosis,hypersensitive syndrome and pain. More preferably, the neurologicalcondition is Alzheimer's disease.

The invention also concerns a pharmaceutical composition comprising aneffective amount of a compound of formula I, an inhibitor of formula I,a dimeric inhibitor as defined above, a pharmaceutically acceptable saltthereof or a prodrug thereof. The pharmaceutical composition mentionedabove may be administered in any suitable way, for example orally orparenterally, and it may be presented in any suitable form such as inthe form of tablets, capsules, powders, syrups or solutions ordispersions for injection.

The present invention also concerns the use of a compound of formula Ifor affinity chromatography. The compound of formula I can be fixed onappropriate support material, for example polymeric resins, throughintroduction at the position 9 of a reactive linker suitable for thecovalent grafting onto the polymeric support, such as an amine. Suchaffinity resins containing appropriately functionalized Huprine offormula I are very useful for the purification of the large scaleproduced BuChE or AChE.

The invention also concerns the use of a compound of formula I asenantioselective catalyst. The compound of formula I have a4-aminopyridine type structure close to the structure ofN,N-dimethylaminopyridine (DMAP). The appropriate functionalization ofthe position 9 offers the possibility to obtain catalysts having both aLewis base part (4-aminopyridine) and a Brønsted acid, Lewis acid oranother Lewis base on the substituent on position 9.

The following examples illustrate different method for preparing thecompounds of the present invention. These examples represent specificembodiments of the invention and are not intended as limiting the scopeof the invention.

In general, column chromatography purifications were performed on silicagel (40-63 μm) from SdS. Thin-layer chromatography (TLC) was carried outon Merck DC Kieselgel 60 F-254 aluminium sheets. Compounds werevisualized by one of the two following methods: (1) illumination with ashort wavelength UV lamp (λ=254 nm) or (2) staining with a 3.5% (w/v)phosphomolybdic acid solution in absolute ethanol. All solvents weredried following standard procedures (CH₂Cl₂, 1,2-dichloroethane andCH₃CN: distillation over P₂O₅, DMF and DMSO: distillation over BaO underreduced pressure, THF, toluene and Et₂O: distillation overNa/benzophenone). Triethylamine (TEA) and pyridine were distilled fromCaH₂ and stored over BaO or KOH.

Melting points were recorded on a LEICA VMHB Kofler system atatmospheric pressure and were uncorrected. Microanalyses were carriedout on Carlo-Erba 1106. Infrared spectra were recorded as KBr pelletsusing a Perkin Elmer FT-IR Paragon 500 spectrometer with frequenciesgiven in reciprocal centimeters (cm⁻¹). ¹H and ¹³C NMR spectra wererecorded on a Bruker DPX 300 spectrometer (Bruker, Wissembourg, France).Chemical shifts are expressed in parts per million (ppm) fromCDCl₃(δ_(H)=7.26, δ_(C)=77.16), DMSO-d₆(δ_(H)=2.50, δ_(C)=39.52) orCD₃OD (δ_(H)=3.31, δ_(C)=49.00). ¹J values are expressed in Hz. Massspectra were obtained with a Finnigan LCQ Advantage MAX (ion trap)apparatus equipped with an electrospray source. All analyses wereperformed in the positive mode.

Analytical HPLC was performed on a Thermo Electron Surveyor instrumentequipped with a PDA detector under the following conditions: ThermoHypersil GOLD C18 column (5μ, 4.6×150 mm) with CH₃CN and 0.1% aqueousTFA as eluents [90% TFA (5 min), linear gradient from 0 to 100% of CH₃CN(40 min)] at a flow rate of 1.0 mL·min⁻¹ dual UV detection at 254 and270 nm. Two chromatographic systems were used for the preparative HPLCpurification steps:

System A: reversed-phase HPLC (C18, Thermo Hypersil GOLD, 5μ, 21.2×250mm) with CH₃CN and trifluoroacetic acid 0.1% (TFA 0.1%, pH 2.0) as theeluents [100% TFA (5 min), then linear gradient from 0 to 100% (50 min)of CH₃CN] at a flow rate of 20.0 mL/min. UV-Visible detection wasachieved at 264 nm.

System B: reversed-phase HPLC (C18, Thermo Hypersil GOLD, 5μ, 21.2×250mm) with MeOH and trifluoroacetic acid 0.1% (TFA 0.1%, pH 2.0) as theeluents [100% TFA (5 min), then linear gradient from 0% to 20% (10 min)of MeOH, then linear gradient from 20% to 100% (40 min) of MeOH] at aflow rate of 15.0 mL/min. UV-Visible detection was achieved at 264 nm.

EXAMPLE 1 Ethyl(12-Amino-3-chloro-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinolin-9-yl)acetate(HUP 1) Preparation of tetramethyl 3,7-Dihydroxybicyclo[3.3.1]nona-2,6-diene-2,4,6,8-tetracarboxylate

A mixture of 1,1,3,3 tetramethoxypropane (32.8 g, 0.20 mol) and 2 M HCl(100 mL) was stirred for 1.5 h at room temperature. To this mixturecooled at 0° C. was added successively and carefully an aqueous solutionof 5 M NaOH within 30 min (pH=8) and MeOH (100 mL). At 0° C.,dimethyl-3-oxoglutarate (69.6 g, 0.40 mol) was added, followed byaddition of MeOH (70 mL). The reaction mixture was allowed to warm toroom temperature and stirred for 3 days. The reaction mixture wasacidified to pH=3 with 10 M HCl. Filtrating fractionwise, washing withwater and drying at the dessicator afford the desired tetra ester as awhite solid (39.2 g, 51%).

Preparation of bicyclo [3.3.1]nonane-3,7-dione (1)

A suspension of tetramethyl3,7-dihydroxybicyclo[3.3.1]nona-2,6-diene-2,4,6,8-tetracarboxylate (19.2g, 50 mmol) in an aqueous solution of 10 M HCl (50 mL), water (50 mL)and glacial acetic acid (100 mL) was heated at 130° C. for 6 h. Aftercooling at room temperature, the reaction mixture was poured ontocrushed ice (200 mL) and extracted with DCM (4×200 mL). The combinedorganic layers were washed with an aqueous saturated solution of NaHCO₃.The organic layer was dried over MgSO₄, and concentrated under reducedpressure to give an orange solid. This crude product was dissolved inacetone and the salts which precipitated were filtered. Concentration ofthe filtrate and washing with Et₂O afford the desired diketone (1) as awhite solid (6.5 g, 85%).

Preparation of ethyl(3-Hydroxy-2-oxatricyclo[3.3.1.13,7]dec-1-yl)acetate (2)

Zn solid was activated just prior to perform Reformatsky reaction asfollowed: Zn dust was stirred at r.t. in 2 M aqueous HCl solution untilthe bubbling ceased (≈40 min for 15 g Zn). The solid was then filteredand washed with water (50 mL), the EtOH (50 mL), acetone (50 mL), thenEt₂O (50 mL) and the thin solid was heated using an air gun under vacuumto complete drying. Reformasky reaction: to a suspension of suchactivated Zn* solid (2.29 g, 35 mmol) in dry THF (70 mL) warmed toreflux temperature under argon was added dropwise through the condenserover 40 min a mixture of ethylbromoacetate (1.75 mL, 15 mmol) anddiketone (1) (0.761 g, 5 mmol) in dry THF (125 mL). The green mixturewas stirred at reflux temperature for 5 h, then cooled to r.t. andhydrolyzed by quite slow addition of saturated aqueous NH₄Cl solution(until pH=5-6): the resulting colorless solution with the Zn solidfloating around was stirred for 10 min at r.t. before extraction withDCM (3×80 mL). The combined org. layers were washed with saturatedsolution of NaHCO₃ (80 mL), then brine (80 mL), then water (80 mL),dried with MgSO₄ and concentrated under reduced pressure to afford anorange oil. This crude product was then filtered trough a plug of silicagel and washed with AcOEt/cyclohexane mixtures, then with pure AcOEt toafford the desired acetal (2) as yellow oil pure enough to carry on thesynthesis. A purer product can be obtained as white crystals (1.044 g,87%) after flash chromatography (AcOEt/cyclohexane 4/6, v/v).

Preparation of ethyl{3-[(Methylsulfonyl)oxy]-2-oxatricyclo[3.3.1.13,7]dec-1-yl}acetate (3)

A solution of adamantanol (2) (600 mg, 2.5 mmol) and triethylamine (540μL, 3.75 mmol) in dry DCM (12 mL) under argon was cooled to 0° C.Methane sulfonyl chloride (290 μL, 3.75 mmol) was then added dropwiseand the cooling bath was allowed to melt. After 30 min stirring, thesolution was carefully poured onto a mixture of 2 M aqueous HCl solution(20 mL) and crushed ice. The organic layer was separated and the aqueousone extracted with DCM (3×20 mL). The combined organic layers werewashed with saturated solution of NaHCO₃ (20 mL), then brine (20 mL),then water (20 mL), dried with MgSO₄ and concentrated under reducedpressure to afford an orange oil. This crude product is then filteredtrough a plug of silica gel and washed with AcOEt/cyclohexane 3/7, v/vmixture to afford the desired methanesulfonate as quite yellow oil (800mg, quantitative). Purification by flash chromatography(AcOEt/cyclohexane 2/8, v/v) afforded the desired product (3) as whitecrystals (755 mg, 95%).

Preparation of ethyl (7-Oxobicyclo[3.3.1]non-2-en-3-yl)acetate (4)

Method 1

A mixture of mesylate (3) (4.0 g, 12.55 mmol) and dry silica (40-63 μm,dried in oven at 110° C. for at least 12 h) in distilled1,2-dichloroethane (40 mL) was stirred under argon at reflux temperaturefor 18 h. The cooled reaction mixture was then filtered and the residuewashed with AcOEt/cyclohexane 3/7, v/v. Concentration of the dark pinkfiltrate then purification by chromatography (AcOEt/cyclohexane 0/10 to3/7, v/v) afforded a colorless oil (910 mg, 4.094 mmol) along with somehydrolysed product adamantanol (2) (135 mg, 0.561 mmol), ratio desiredenone (4)/adamantanol (2) 8.5/1, global yield 37% over 3 steps.

Method 2

A mixture of mesylate (3) (1.435 g, 4.5 mmol) and anhydrous aluminiumtrichloride (720 mg, 5.4 mmol) in distilled 1,2-dichloroethane (12 mL)was stirred was stirred under argon at reflux temperature for 10 minthen cooled to r.t. The reaction mixture was diluted with water (24 mL)and THF (24 mL), made basic with 5 M NaOH (30 mL) and stirred at r.t. 30min before extraction with DCM (2×50 mL), then with AcOEt (2×50 mL). Thecombined organic layers were dried with MgSO₄ and concentrated underreduced pressure to afford a pale yellow oil. Purification by flashchromatography (AcOEt/cyclohexane 0/10 to 3/7, v/v) afforded the desiredenone (4) as colorless oil (920 mg, 92%).

Preparation of ethyl(12-Amino-3-chloro-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinolin-9-yl)acetate(HUP 1)

Method 1 (from ethyl (7-Oxobicyclo[3.3.1]non-2-en-3-yl)acetate (4)):

To a suspension of anhydrous AlCl₃ (980 mg, 7.35 mmol) and4-chloro-2-aminobenzonitrile (1.12 g, 7.35 mmol) in distilled1,2-dichloroethane (10 mL) under argon was added a solution of enone (4)(1.09 g, 4.9 mmol) in dry 1,2-dichloroethane (10 mL) dropwise over 10min at r.t. The reaction mixture was stirred at reflux for 14 h thencooled to r.t. The solution was diluted with water (25 mL) and THF (25mL), basified by addition of 5 M NaOH solution (30 mL) and stirred atr.t. for 30 min. The solution was then extracted with DCM (2×50 mL) thenwith AcOEt (3×50 mL). The combined organic layers were dried with MgSO₄and concentrated to afford a yellow solid. Purification by flashchromatography (cyclohexane/AcOEt 1/1 to AcOEt/MeOH 95/5, v/v) affordedthe desired Huprine (HUP 1) as a pale yellow solid (1.59 g, 91%).

Method 2 (from 3-ethylacetate-2-oxa-1-adamantyl methanesulfonate (3)):

A suspension of anhydrous AlCl₃ (417 mg, 3.13 mmol) and mesylate (3)(830 mg, 2.6 mmol) in dry 1,2-dichloroethane (4 mL) was stirred atreflux. The reaction mixture became orange and exothermic. After 5minutes, a suspension of 4-chloro-2-aminobenzonitrile (438 mg, 2.87mmol) in dry 1,2-dichloroethane (5 mL) was added dropwise to therefluxing mixture and the reflux was maintained for 8 h. The reactionmixture was then cooled to r.t., diluted with water (10 mL) and THF (10mL), basified by addition of 5 M NaOH solution (10 mL) and stirred atr.t. for 30 min. The phases were separated (DCM was added if necessary)and the aqueous layer was extracted with AcOEt (3×20 mL). The combinedorganic layers were dried with Na₂SO₄ and concentrated under reducedpressure to afford a yellow solid. Purification by flash chromatography(cyclohexane/AcOEt 10/0 to AcOEt/MeOH 9/1, v/v) afforded a pale yellowsolid. Recrystallisation from petroleum ether/AcOEt, 8/2, v/v affordedthe desired Huprine (HUP 1) as a white solid (799 mg, 88%).

Rf (AcOEt/MeOH 9/1, v/v)=0.33.

m.p.=179-180° C.

IR (KBr): ν=3352, 3209, 2929, 1727, 1648, 1609, 1559, 1490, 1426, 1371,1308, 1285, 1258, 1154, 1031, 929 cm⁻¹.

¹H NMR (300 MHz, CDCl₃): δ=0.99 (t, J=7.2 Hz, 3H, H₁₈), 1.88-1.93 (m,1H, H₁₀), 2.02-2.08 (m, 2H, H₁₀, H₁₃), 2.57 (dd, J=17.1 Hz, J=3.9 Hz,1H, H₁₃), 2.70-2.74 (m, 1H, H₇), 2.72-2.77 (m, 2H, H₁₄), 2.94 (d, J=17.7Hz, 1H, H₆), 3.11 (dd, J=17.5 Hz, J=5.5 Hz, 1H, H₆), 3.16-3.20 (m, 1H,H₁₁), 3.92 (q, J=7.1 Hz, 2H, H₁₇), 5.05 (brs, 2H, NH₂), 5.67 (d, J=5.1Hz, 1H, H₈), 7.21 (dd, J=9.0 Hz, J=1.9 Hz, 1H, H₂), 7.65 (d, J=9.0 Hz,1H, H₁), 7.81 (d, J=1.9 Hz, 1H, H₄).

¹³C NMR (75 MHz, CDCl₃): δ=14.0 (C₁₈), 27.4 (C₁₁), 28.4 (C₇), 28.8(C₁₀), 33.9 (C₁₃), 39.2 (C₆), 43.3 (C₁₄), 60.6 (C₁₇), 114.9 (C_(11a) orC_(12a)), 115.8 (C_(11a) or C_(12a)), 121.9 (C₁), 124.7 (C₂), 127.1(C₄), 129.5 (C₈), 129.8 (C₉), 134.6 (C₃), 146.4 (C_(4a) or C₁₂), 146.9(C_(4a) or C₁₂), 158.1 (C_(5a)), 171.5 (C₁₅).

MS (ESI+): m/z (%): 357.33 (100) [M+H]⁺, 359.20 (36).

IC₅₀ rh-AChE: 3.90±0.50 nM.

IC₅₀ rh-BuChE: 137±11 nM.

IC₅₀ erythrocyte h-AChE: 38.3 nM.

EXAMPLE 22-(12-Amino-3-chloro-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinolin-9-yl)Ethanol (HUP 2)

To a cooled (0° C.) stirred suspension of anhydrous LiAlH₄ (400 mg, 10mmol) in dry THF (50 mL) was added dropwise a solution of ester (HUP 1)(1.78 g, 5.0 mmol) in dry THF (15 mL). The solution was stirred 1 h (0°C. to r.t.) then quenched carefully at 0° C. by the addition of water(1.75 mL), then 5 M NaOH solution (1.75 mL), then water (5 mL). Thereaction mixture was stirred 10 min at r.t. then dried with Na₂SO₄.Filtration and concentration afforded the desired Huprine (HUP 2) as avery pale yellow solid (1.60 g, quantitative). Recrystallisation fromacetone afforded a white solid.

Rf (AcOEt/MeOH 8/2, v/v)=0.15.

m.p.=174° C. (decomposition).

IR (KBr): ν=3352, 3252, 2894, 1645, 1609, 1573, 1490, 1424, 1373, 1309,1285, 1046, 928, 818, 770 cm⁻¹.

¹H NMR (300 MHz, MeOD): δ=1.84-1.89 (m, 1H, H₁₀), 2.00-2.06 (m, 4H, H₁₀,H₁₃, H₁₄), 2.49 (dd, J=17.3 Hz, J=4.1 Hz, 1H, H₁₃), 2.65-2.69 (m, 1H,H₇), 2.82 (d, J=17.5 Hz, 1H, H₆), 3.02 (dd, J=17.5 Hz, J=5.6 Hz, 1H,H₆), 3.27-3.31 (m, 1H, H₁₁), 3.46 (t, J=7.0 Hz, 2H, H₁₅), 5.57 (d, J=4.9Hz, 1H, H₈), 7.23 (dd, J=9.0 Hz, J=1.9 Hz, 1H, H₂), 7.64 (d, J=1.9 Hz,1H, H₄), 7.99 (d, J=9.0 Hz, 1H, H₁).

¹³C NMR (75 MHz, MeOD): δ=28.3 (C₁₁), 29.6 (C₇), 30.2 (C₁₀), 35.2 (C₁₃),40.2 (C₆), 42.6 (C₁₄), 61.5 (C₁₅), 115.5 (C_(11a) or C_(12a)), 117.1(C_(11a) or C_(12a)), 124.6 (C₁), 124.8 (C₂), 126.3 (C₄), 127.3 (C₈),135.0 (C₃), 135.5 (C₉), 148.0 (C_(4a) or C₁₂), 150.0 (C_(4a) or C₁₂),159.2 (C_(5a)).

MS (ESI+): m/z (%): 315.27 (100) [M+H]⁺, 317.27 (35).

IC₅₀ rh-AChE: 1.05±0.13 nM.

IC₅₀ rh-BuChE: 1240 nM.

IC₅₀ erythrocyte h-AChE: 6.15 nM.

EXAMPLE 33-Chloro-9-vinyl-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinolin-12-amineTrifluoroacetic Acid (HUP 3)

To a partially soluble suspension of iodinated compound (HUP 7) (71 mg,0.167 mmol) in MeCN (2 mL) was added a solution of 1 M trimethylamine inTHF (1.7 mL, 1.67 mmol), and the mixture was heated to 55° C. for 13 h.The reaction mixture was concentrated to dryness then purified bypreparative HPLC (System A) and freeze dried to afford thedi-trifluoroacetate salt of the desired Huprine (HUP 3) as a white solid(37.7 mg, 55%) along with quaternary ammonium (HUP 25) (26.3 mg, 27%) assubstitution byproduct.

Rf (AcOEt/MeOH 8/2, v/v)=0.38.

m.p.=150° C. (decomposition).

¹H NMR (300 MHz, MeOD): δ=1.98-2.04 (m, 1H, H₁₀), 2.09-2.16 (m, 1H,H₁₀), 2.31-2.37 (m, 1H, H₁₃), 2.53-2.62 (m, 1H, H₁₃), 2.88-2.97 (m, 2H,H₇, H₆), 3.23-3.29 (m, 1H, H₆), 3.46-3.49 (m, 1H, H₁₁), 4.86-4.91 (m,1H, H₁₅), 5.09 (d, J=17.5 Hz, 1H, H₁₅), 5.90 (d, J=5.5 Hz, 1H, H₈), 6.30(dd, J=17.5 Hz, J=10.7 Hz, 1H, H₁₄), 7.56 (dd, J=9.0 Hz, J=1.5 Hz, 1H,H₂), 7.71 (d, J=1.5 Hz, 1H, H₄), 8.34 (d, J=9.0 Hz, 1H, H₁).

¹³C NMR (75 MHz, MeOD): δ=26.9 (C₁₁), 28.4 (C₇), 29.4 (C₁₀), 29.9 (C₁₃),35.4 (C₆), 112.1 (C₁₅), 115.2 (C_(11a) or C_(12a)), 115.3 (C_(11a) orC_(12a)), 119.2 (C₄), 126.3 (C₁), 127.7 (C₂), 132.1 (C₈), 136.5 (C₃),139.5 (C₉), 140.3 (C₁₄), 140.5 (C_(4a) or C₁₂), 152.7 (C_(4a) or C₁₂),156.8 (C_(5a)).

MS (ESI+): m/z (%): 297.33 (100) [M+H]⁺, 299.26 (32).

IC₅₀ rh-AChE: 1.32±0.17 nM.

IC₅₀ rh-BuChE: 180±13 nM.

IC₅₀ erythrocyte h-AChE: 405 nM.

EXAMPLE 42-(12-Amino-3-chloro-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinolin-9-yl)ethylAcetate (HUP 4)

To a cooled to 0° C. solution of alcohol (HUP 2) (78.5 mg, 0.25 mmol)and triethylamine (840 μL, 6 mmol) in THF (4 mL) was added dropwiseacetic anhydride (570 μL, 6 mmol) and the resulting suspension wasstirred at reflux for 21 h. The reaction mixture was partionned between2 M aqueous HCl solution (12 mL) and AcOEt (15 mL). The aqueous phasewas extracted with AcOEt (2×15 mL). The combined organic layers weredried with Na₂SO₄ and concentrated under reduced pressure to afford abrown residue. Purification by flash chromatography (AcOEt/MeOH 10/0 to8.5/1.5 v/v) to afford the desired Huprine (HUP 4) as a white solid (16mg, 18%) along with tri-acylated product N,N-diacyl-HUP 4 (66 mg, 60%).

Rf (AcOEt/MeOH 8/2, v/v)=0.45.

m.p.=97° C. (decomposition).

¹H NMR (300 MHz, CDCl₃): δ=1.80 (s, 3H, Ac), 1.89-2.00 (m, 3H, H₁₀,H₁₃), 2.05-2.12 (m, 2H, H₁₄), 2.45 (dd, J=17.3 Hz, J=4.3 Hz, 1H, H₁₃),2.72-2.76 (m, 1H, H₇), 2.93 (d, J=17.7 Hz, 1H, H₆), 3.05-3.15 (m, 2H,H₆, H₁₁), 3.91-3.99 (m, 2H, H₁₅), 5.55 (d, J=5.3 Hz, 1H, H₈), 5.71 (brs,2H, NH₂), 7.23 (dd, J=9.0 Hz, J=1.9 Hz, 1H, H₂), 7.77 (d, J=9.0 Hz, 1H,H₁), 7.81 (d, J=1.9 Hz, 1H, H₄).

¹³C NMR (75 MHz, CDCl₃): δ=20.8 (Ac), 27.1 (C₁₁), 27.9 (C₇), 28.8 (C₁₀),33.6 (C₁₃), 36.4 (C₁₄), 37.9 (C₆), 62.4 (C₁₅), 114.5 (C_(11a) orC_(12a)), 115.3 (C_(11a) or C_(12a)), 122.8 (C₁), 124.8 (C₂), 125.1(C₄), 127.2 (C₈), 132.6 (C₃), 135.6 (C₉), 144.4 (C_(4a) or C₁₂), 148.3(C_(4a) or C₁₂), 156.4 (C_(5a)), 171.0 (C═O).

MS (ESI+): m/z (%): 357.27 (100) [M+H]⁺, 359.20(36).

IC₅₀ rh-AChE: 1.44±0.18 nM.

IC₅₀ rh-BuChE: 37% at 1 μM.

IC₅₀ erythrocyte h-AChE: 12.0 nM.

EXAMPLE 52-[3-Chloro-12-(diacetylamino)-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinolin-9-yl]ethyl Acetate (N,N-diacyl-HUP 4)

To a cooled to 0° C. solution of alcohol (HUP 2) (78.5 mg, 0.25 mmol)and triethylamine (840 μL, 6 mmol) in THF (4 mL) was added dropwiseacetic anhydride (570 μL, 6 mmol) and the resulting suspension wasstirred at reflux for 21 h. The reaction mixture was partionned between2 M aqueous HCl solution (12 mL) and AcOEt (15 mL). The aqueous phasewas extracted with AcOEt (2×15 mL). The combined organic layers weredried with Na₂SO₄ and concentrated under reduced pressure to afford abrown residue. Purification by flash chromatography(cyclohexane/AcOEt/MeOH 7/3/0 to 0/8.5/1.5 with a 1% Et₃N, v/v) affordedthe desired Huprine as a pale yellow solid (66 mg, 60%) along withmono-acylated product (HUP 4) (16 mg, 18%).

Rf (AcOEt)=0.85.

m.p.=50° C. (decomposition).

¹H NMR (300 MHz, CDCl₃): δ=1.79-1.90 (m, 2H, H₁₀, H₁₃), 1.86 (s, 3H,OAc), 2.07 (s, 3H, NAc), 2.07-2.10 (m, 3H, H₁₀, H₁₄), 2.44-2.53 (m, 1H,H₁₃), 2.52 (s, 3H, NAc), 2.80-2.85 (m, 1H, H₇), 3.18-3.28 (m, 3H, H₆,H₁₁), 3.91-3.99 (m, 2H, H₁₅), 5.63 (d, J=4.7 Hz, 1H, H₈), 7.44-7.45 (m,2H, H₂, H₁), 8.03-8.04 (m, 1H, H₄).

¹³C NMR (75 MHz, CDCl₃): δ=20.9 (OAc), 25.9 (NAc), 27.0 (NAc), 28.1(C₇), 28.5 (C₁₀), 29.2 (C₁₁), 34.6 (C₁₃), 36.1 (C₁₄), 40.3 (C₆), 62.3(C₁₅), 123.0 (3C, C_(11a), C_(12a), C₁), 127.4 (C₈), 128.2 (C₄), 128.5(C₂), 132.0 (C₃), 133.1 (C₉), 141.9 (C_(4a) or C₁₂), 148.2 (C_(4a) orC₁₂), 161.2 (C_(5a)), 171.0 (C═O), 172.1 (C═O), 173.0 (C═O).

MS (ESI+): m/z (%): 441.16 (100) [M+H]⁺, 443.09 (33), 399.25 (15).

EXAMPLE 62-(12-Amino-3-chloro-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinolin-9-yl)ethylTrifluoroacetate (HUP 5)

To a cooled to 0° C. solution of alcohol (HUP 2) (78.5 mg, 0.25 mmol)and triethylamine (53 μL, 0.375 mmol) in THF (4 mL) was added dropwisetrifluoroacetic anhydride (52 μL, 0.375 mmol). The solution was stirred40 min at r.t. The reaction mixture was concentrated under reducedpressure to dryness then partionned between 2M aqueous HCl solution (12mL) and AcOEt (12 mL). The aqueous phase was extracted with AcOEt (3×15mL). The combined organic layers were dried with Na₂SO₄ and concentratedunder reduced pressure to afford a yellow solid. Purification by flashchromatography (cyclohexane/AcOEt 7/3, v/v) afforded the desired Huprine(HUP 5) as a white solid (85 mg, 83%).

Rf (cyclohexane/AcOEt 1/1, v/v)=0.59.

m.p.=124° C. (decomposition).

¹H NMR (300 MHz, MeOD): δ=1.98-2.08 (m, 3H, H₁₀, H₁₃), 2.23-2.30 (m, 2H,H₁₄), 2.63 (dd, J=17.4 Hz, J=4.8 Hz, 1H, H₁₃), 2.11-2.17 (m, 1H, H₇),3.17 (d, J=18.3 Hz, 1H, H₆), 3.39 (dd, J=18.3 Hz, J=5.3 Hz, 1H, H₆),3.58-3.64 (m, 1H, H₁₁), 4.23-4.31 (m, 2H, H₁₅), 5.69 (d, J=5.1 Hz, 1H,H₈), 7.72 (dd, J=9.0 Hz, J=1.7 Hz, 1H, H₂), 7.97 (d, J=9.0 Hz, 1H, H₁),8.05 (d, J=1.7 Hz, 1H, H₄).

¹³C NMR (75 MHz, MeOD): δ=28.4 (C₁₀), 28.5 (C₇), 29.8 (C₁₁), 35.8 (C₁₃),37.0 (C₁₄), 38.5 (C₆), 66.5 (C₁₅), 116.8 (q, J=140.2 Hz, CF₃), 123.3(C₄), 124.5 (C_(11a) or C_(12a)), 126.6 (C₁), 129.3 (C₈), 130.3 (C₂),133.6 (C_(11a) or C_(12a)), 135.0 (C₃), 139.6 (C₉), 143.5 (C_(4a) orC₁₂), 146.6 (C_(4a) or C₁₂), 158.1 (C_(5a)), 160.9 (C═O).

¹⁹F NMR (282 MHz, MeOD): −77.13, −76.75, −76.31.

MS (ESI+): m/z (%): 315.40 (100) [M+H—COCF₃]⁺, 317.33 (37).

IC₅₀ rh-AChE: 1.69±0.16 nM.

IC₅₀ rh-BuChE: 1360 nM.

IC₅₀ erythrocyte h-AChE: 27.5 nM.

EXAMPLE 73-Chloro-9-(2-methoxyethyl)-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinolin-12-amine(HUP 6)

To a solution of sodium pieces (about 50 mg, degreased in Et₂O) in MeOH(25 mL) was added at 0° C. dropwise over 5 min a solution of alcohol(HUP 2) (118 mg, 0.3 mmol) in MeOH (5 mL). The resulting solution wasstirred 1 h at r.t., then at reflux for 24 h without change in TLC and¹H NMR. Water (3 mL) was added and the reaction mixture was concentratedto remove the methanol. The residue was partitioned between AcOEt andwater (20 mL of each) and the aqueous phase was extracted with AcOEt(2×15 mL). The combined organic layers were dried with Na₂SO₄ andconcentrated under reduced pressure to afford a yellow solid.Purification by flash chromatography (AcOEt/MeOH 100/0 to 85/15, v/v)afforded the desired Huprine (HUP 6) as a white solid (43.1 mg, 44%)along with alkene (HUP 3) (6.9 mg, 7.7%) as β-elimination by-product.

Rf (AcOEt/MeOH 8/2, v/v)=0.31.

m.p.=124° C. (decomposition).

IR (KBr): ν=3364, 3248, 2928, 1645, 1609, 1560, 1490, 1425, 1371, 1309,1285, 1217, 1184, 1154, 1110, 928, 756 cm⁻¹.

¹H NMR (300 MHz, MeOD): δ=1.89-1.94 (m, 1H, H₁₀), 2.03-2.09 (m, 4H, H₁₀,H₁₃, H₁₄), 2.48 (dd, J=18.5 Hz, J=5.5 Hz, 1H, H₁₃), 2.69-2.73 (m, 1H,H₇), 2.83 (d, J=17.5 Hz, 1H, H₆), 3.06 (dd, J=17.5 Hz, J=5.5 Hz, 1H,H₆), 3.13 (s, 3H, MeO), 3.26-3.33 (m, 3H, H₁₁, H₁₅), 5.58 (d, J=5.5 Hz,1H, H₈), 7.30 (dd, J=9.0 Hz, J=1.9 Hz, 1H, H₂), 7.66 (d, J=1.9 Hz, 1H,H₄), 8.06 (d, J=9.0 Hz, 1H, H₁).

¹³C NMR (75 MHz, MeOD): δ=28.3 (C₁₁), 29.6 (C₇), 30.2 (C₁₀), 35.0 (C₁₃),38.4 (C₁₄), 39.8 (C₆), 58.7 (MeO), 72.3 (C₁₅), 115.6 (C_(11a) orC_(12a)), 117.0 (C_(11a) or C_(12a)), 124.9 (C₁), 125.3 (C₂), 125.6(C₄), 127.2 (C₈), 135.4 (C₃), 136.2 (C₉), 147.2 (C_(4a) or C₁₂), 150.8(C_(4a) or C₁₂), 158.7 (C_(5a)).

MS (ESI+): m/z (%): 329.33 (100) [M+H]⁺, 331.26 (37).

IC₅₀ rh-AChE: 1.75±0.21 nM.

IC₅₀ rh-BuChE: 401±26 nM.

IC₅₀ erythrocyte h-AChE: 4.50 nM.

EXAMPLE 83-Chloro-9-(2-iodoethyl)-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinolin-12-amine(HUP 7)

To a stirred suspension of sodium iodide (1.35 g, 9 mmol) in acetone (10mL) was added mesylate (HUP 13) (648 mg, 1.65 mmol) in acetone (7 mL).The reaction mixture was stirred at reflux for 12 h. The mesylate saltswere filtered and the filtrate was concentrated under reduced pressureto give a yellow solid. This solid was redissolved acetone/AcOEtmixtures to precipitate the excess of sodium iodide. Filtration of thesalts and evaporation of the filtrate afford the desired Huprine (HUP 7)as a pale yellow solid (378 mg, 54%) along with alkene (HUP 3) (64 mg,13%) as β-elimination by-product.

Rf (AcOEt/MeOH 8/2, v/v)=0.40.

m.p.=111° C. (decomposition).

¹H NMR (300 MHz, MeOD): δ=1.84-2.03 (m, 3H, H₁₀, H₁₃), 2.26-2.33 (m, 2H,H₁₄), 2.43 (dd, J=21.3 Hz, J=4.7 Hz, 1H, H₁₃), 2.67-2.72 (m, 1H, H₇),2.85 (d, J=17.5 Hz, 1H, H₆), 3.00-3.07 (m, 2H, H₆, H₁₁), 3.18-3.23 (m,2H, H₁₅), 5.58 (d, J=4.9 Hz, 1H, H₈), 7.26 (dd, J=8.9 Hz, J=2.1 Hz, 1H,H₂), 7.64 (d, J=2.1 Hz, 1H, H₄), 8.02 (d, J=8.9 Hz, 1H, H₁).

MS (ESI+): m/z (%): 425.20 (100) [M+H]⁺, 427.13 (32), 297.27 (17).

IC₅₀ rh-AChE: 2.70±0.82 nM.

IC₅₀ rh-BuChE: 141±7 nM.

EXAMPLE 93-(12-Amino-3-chloro-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinolin-9-yl)propanenitrileTrifluoroacetic Acid (HUP 8)

To a solution of mesylate (HUP 13) (98 mg, 0.25 mmol) was added a apartially soluble suspension of potassium cyanide (81.4 mg, 1.25 mmol)and TBAI (30 mg, 0.3 mmol) in a MeCN/DMF/DMSO mixture (6 mL/3 mL/2 mL).The resulting suspension was stirred 5 h at 70° C. The reaction mixturewas concentrated to dryness then purified by preparative HPLC (System A)and freeze dried to afford the trifluoroacetate salt of the desiredHuprine (HUP 8) as a white solid (62.2 mg, 57%).

m.p.=127° C. (decomposition).

¹H NMR (300 MHz, MeOD): δ=1.91-2.15 (m, 3H, H₁₀, H₁₃), 2.16-2.21 (t,J=6.9 Hz, 2H, H₁₄), 2.44 (td, J=7.2 Hz, J=2.1 Hz, 2H, H₁₅), 2.56 (dd,J=21.3 Hz, J=5.5 Hz, 1H, H₁₃), 2.85-2.94 (m, 2H, H₇, H₆), 3.19-3.26 (m,1H, H₆), 3.41-3.45 (m, 1H, H₁₁), 5.75 (d, J=4.3 Hz, 1H, H₈), 7.56 (dd,J=9.0 Hz, J=1.5 Hz, 1H, H₂), 7.71 (d, J=1.5 Hz, 1H, H₄), 8.34 (d, J=9.0Hz, 1H, H₁).

¹³C NMR (75 MHz, MeOD): δ=16.4 (C₁₅), 27.4 (C₁₁), 28.2 (C₇), 29.1 (C₁₀),33.1 (C₁₄), 33.4 (C₁₃), 35.8 (C₆), 115.1 (C_(11a) or C_(12a)), 115.4(C_(11a) or C_(12a)), 119.3 (C₄), 120.3 (CN), 126.4 (C₁), 127.7 (C₂),127.8 (C₈), 135.7 (C₃), 139.6 (C₉), 140.4 (C_(4a) or C₁₂), 153.0 (C_(4a)or C₁₂), 156.8 (C_(5a)).

MS (ESI+): m/z (%): 324.27 (100) [M+H]⁺, 326.27 (38).

IC₅₀ rh-AChE: 3.15±0.42 nM.

IC₅₀ rh-BuChE: 514±58 nM.

EXAMPLE 103-Chloro-9-(2-chloroethyl)-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinolin-12-amineTrifluoroacetic Acid (HUP 9)

To a partially soluble suspension of alcohol (HUP 2) (63 mg, 0.2 mmol)in AcOEt (10 mL) cooled to 0° C. was added dropwise thionyl chloride(300 μL, 4.14 mmol). The reaction mixture was stirred 14 h at 60° C.,then concentrated to dryness. The residue was purified by preparativeHPLC (System A) and freeze dried to afford the trifluoroacetate salt ofthe desired Huprine (HUP 9) as a white solid (22.0 mg, 25%).

Rf (AcOEt/MeOH 8/2, v/v)=0.44 (free base).

m.p.=132° C. (decomposition).

¹H NMR (300 MHz, MeOD): δ=1.96-2.13 (m, 3H, H₁₀, H₁₃), 2.28-2.34 (m, 2H,H₁₄), 2.53 (dd, J=17.2 Hz, J=4.5 Hz, 1H, H₁₃), 2.84-2.92 (m, 2H, H₁₁,H₆), 3.18-3.25 (m, 1H, H₆), 4.06-4.10 (m, 1H, H₇), 3.49 (t, J=6.7 Hz,2H, H₁₅), 5.69 (d, J=4.3 Hz, 1H, H₈), 7.57 (dd, J=9.0 Hz, J=1.7 Hz, 1H,H₂), 7.74 (d, J=1.7 Hz, 1H, H₄), 8.34 (d, J=9.0 Hz, 1H, H₁).

¹³C NMR (75 MHz, MeOD): δ=27.5 (C₇), 28.3 (C₇), 29.2 (C₁₀), 33.6 (C₁₃),35.9 (C₆), 40.9 (C₁₄), 43.6 (C₁₅), 115.3 (C_(11a) or C_(12a)), 115.4(C_(11a) or C_(12a)), 119.3 (C₄), 126.4 (C₁), 127.7 (C₂), 127.9 (C₈),135.3 (C₃), 139.7 (C₉), 140.5 (C_(4a) or C₁₂), 153.1 (C_(4a) or C₁₂),156.8 (C_(5a)).

MS (ESI+): m/z (%): 333.33 (100) [M+H]⁺, 335.20 (62), 337.20 (12).

IC₅₀ rh-AChE: 3.56±0.20 nM.

IC₅₀ rh-BuChE: 207±12 nM.

IC₅₀ erythrocyte h-AChE: 5.09 nM.

EXAMPLE 113-Chloro-9-(2-fluoroethyl)-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinolin-12-amine(HUP 10)

To a partially soluble suspension of alcohol (HUP 2) (157 mg, 0.5 mmol)cooled to −78° C. was added dropwise DAST (75 μL, 0.6 mmol). Theresulting suspension was stirred 1 h at r.t., after which the solubilityproved total. The reaction mixture was cooled again to −78° C. and MeOH(200 μL) was added. The solution was additionally stirred for 30 min atr.t. then quenched by saturated solution of NaHCO₃ and extracted withAcOEt (2×15 mL) and DCM (15 mL). The combined organic layers were driedwith Na₂SO₄ and concentrated under reduced pressure to afford a yellowsolid (132 mg). Purification by flash chromatography (AcOEt/MeOH 100/0to 90/10, v/v) afforded the desired Huprine (HUP 10) as a white solid(78 mg, 49%).

Rf (AcOEt/MeOH 8/2, v/v)=0.56.

m.p.=110° C. (decomposition).

¹H NMR (300 MHz, MeOD): δ=1.91-1.94 (m, 1H, H₁₀), 2.01-2.20 (m, 4H, H₁₀,H₁₃, H₁₄), 2.52 (dd, J=17.9 Hz, J=5.5 Hz, 1H, H₁₃), 2.69-2.73 (m, 1H,H₇), 2.84 (d, J=18.2 Hz, 1H, H₆), 3.06 (dd, J=17.5 Hz, J=5.5 Hz, 1H,H₆), 3.33-3.37 (m, 1H, H₁₁), 4.12 (td, J=47.5 Hz, J=6.3 Hz, 2H, H₁₅),5.63 (d, J=5.5 Hz, 1H, H₈), 7.29 (dd, J=1.9 Hz, J=9.0 Hz, 1H, H₂), 7.65(d, J=1.9 Hz, 1H, H₄), 8.05 (d, J=9.0 Hz, 1H, H₁).

¹³C NMR (75 MHz, MeOD): δ=28.2 (C₁₁), 29.5 (C₇), 30.0 (C₁₀), 35.1 (C₁₃),39.3 (d, C₁₄, J=20.3 Hz), 39.6 (C₆), 83.2 (d, C₁₅, J=165.8 Hz), 115.5(C_(11a) or C_(12a)), 116.9 (C_(11a) or C_(12a)), 124.9 (C₁), 125.3(C₂), 125.5 (C₄), 128.1 (C₈), 134.2 (C₃), 136.2 (C₉), 147.1 (C_(4a) orC₁₂), 150.8 (C_(4a) or C₁₂), 158.4 (C_(5a)).

¹⁹F NMR (282 MHz, MeOD): δ=−76.9.

MS (ESI+): m/z (%): 317.36 (100) [M+H]⁺, 319.22 (37), 320.15 (11).

IC₅₀ rh-AChE: 4.16±0.79 nM.

IC₅₀ rh-BuChE: 522±120 nM.

EXAMPLE 12 12-Amino-3-chloro-9-carboxymethyl-6,7,10,11-tetrahydro-7,11methanocycloocta[b]quinoline Hydrochloride (HUP 11)

A suspension of alcohol (HUP 2) (166 mg, 0.47 mmol) in DMF (2 mL) and 2M NaOH solution (23 mL) was heated at reflux for 6 h30. The reactionmixture was then cooled to r.t. and acidified with 2 M aqueous HClsolution (30 mL). The white crystals which appeared in the solution werefiltered and dried at air to afford the hydrochloride of the desiredHuprine (HUP 11) as a white solid (170 mg, 99%).

m.p.=148° C. (decomposition).

IR (KBr): ν=3342, 3236, 2933, 1713, 1657, 1588, 1468, 1415, 1375, 1229,1155, 1084, 933 cm⁻¹.

¹H NMR (300 MHz, MeOD): δ=1.96-2.01 (m, 1H, H₁₀), 2.09-2.19 (m, 2H, H₁₀,H₁₃), 2.59 (dd, J=17.7 Hz, J=3.8 Hz, 1H, H₁₃,), 2.84-2.96 (m, 4H, H₇,H₁₄, H₆), 3.24 (dd, J=18.1 Hz, J=5.5 Hz, 1H, H₆), 3.39-3.43 (m, 1H,H₁₁), 5.74 (d, J=4.5 Hz, 1H, H₈), 7.60 (dd, J=9.0 Hz, J=1.9 Hz, 1H, H₂),7.74 (d, J=1.9 Hz, 1H, H₄), 8.35 (d, J=9.0 Hz, 1H, H₁).

¹³C NMR (75 MHz, MeOD): δ=27.5 (C₁₁), 28.3 (C₇), 28.9 (C₁₀), 34.1 (C₁₃),35.7 (C₆), 43.4 (C₁₄), 115.3 (C_(11a) or C_(12a)), 115.4 (C_(11a) orC_(12a)), 119.2 (C₄), 126.5 (C₁), 127.7 (C₂), 129.1 (C₈), 132.9 (C₃),139.6 (C₉), 140.4 (C_(4a) or C₁₂), 152.9 (C_(4a) or C₁₂), 156.8(C_(5a)), 175.2 (C₁₅).

MS (ESI+): m/z (%): 329.33 (100) [M+H]⁺, 331.27 (31).

HPLC: tr=14.4 (purity 93%).

IC₅₀ rh-AChE: 5.30±1.10 nM.

IC₅₀ rh-BuChE: <1% at 1 μM.

EXAMPLE 139-(2-Azidoethyl)-3-chloro-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinolin-12-amine(HUP 12)

A suspension of mesylate (HUP 13) (236 mg, 0.6 mmol) and sodium azide(146 mg, 2.25 mmol) in dry DMF (3 mL) was stirred under argon at 70° C.for 6 h. The reaction mixture was then cooled to r.t. and water (5 mL)was added under stirring. Additional water (25 mL) was added. Aqueousphase was extracted with AcOEt (3×30 mL) and the combined organic layerswere dried with Na₂SO₄ and concentrated to afford a yellow oil.Purification by flash chromatography (AcOEt/MeOH 100/0 to 95/5, v/v)afforded the desired Huprine (HUP 12) as a pale yellow solid (172 mg,84%).

Rf (AcOEt/MeOH 9/1, v/v)=0.63.

m.p.=106° C. (decomposition).

¹H NMR (300 MHz, MeOD): δ=1.88-1.92 (m, 1H, H₁₀), 2.01-2.10 (m, 4H, H₁₀,H₁₃, H₁₄), 2.48 (dd, J=17.3 Hz, J=4.1 Hz, 1H, H₁₃,), 2.68-2.72 (m, 1H,H₇), 2.84 (d, J=17.3 Hz, 1H, H₆), 3.04 (dd, J=17.3 Hz, J=5.5 Hz, 1H,H₆), 3.15 (td, J=7.0 Hz, J=3.6 Hz, 2H, H₁₅), 3.29-3.33 (m, 1H, H₁₁),5.64 (d, J=5.5 Hz, 1H, H₈), 7.25 (dd, J=9.0 Hz, J=1.9 Hz, 1H, H₂), 7.65(d, J=1.9 Hz, 1H, H₄), 8.02 (d, J=9.0 Hz, 1H, H₁).

¹³C NMR (75 MHz, MeOD): δ=28.2 (C₁₁), 29.7 (C₇), 30.0 (C₁₀), 34.6 (C₁₃),37.7 (C₁₄), 39.9 (C₆), 50.4 (C₁₅), 115.3 (C_(11a) or C_(12a)), 117.0(C_(11a) or C_(12a)), 124.7 (C₁), 124.9 (C₂), 126.1 (C₄), 128.4 (C₈),134.7 (C₃), 135.7 (C₉), 147.9 (C_(4a) or C₁₂), 150.2 (C_(4a) or C₁₂),158.9 (C_(5a)).

MS (ESI+): m/z (%): 340.11 (100) [M+H]⁺, 342.11 (34).

IC₅₀ rh-AChE: 5.56±0.82 nM.

IC₅₀ rh-BuChE: 522±120 nM.

EXAMPLE 142-(12-Amino-3-chloro-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinolin-9-yl)Ethyl Methanesulfonate (HUP 13)

To a cooled (0° C.) stirred solution of alcohol (HUP 2) (944 mg, 3 mmol)and triethylamine (630 μL, 4.5 mmol) in dry THF (25 mL) was addedmethane sulfonyl chloride (350 μL, 4.5 mmol) dropwise over 10 min. Thesolution was stirred 2 h (0° C. to r.t.). The reaction mixture was thenpoured onto a saturated aqueous solution of K₂CO₃ and the aqueous phasewas extracted with AcOEt (3×25 mL). The combined organic layers werewashed with water (30 mL), dried with MgSO₄ and concentrated to afford apale yellow solid (1.20 g, quantitative). Purification by flashchromatography (petroleum ether/AcOEt 3/7 then AcOEt then AcOEt/MeOH8.5/1.5) afforded the desired Huprine (HUP 13) as an off white solid(1.11 g, 94%).

Rf (AcOEt/MeOH 8/2, v/v)=0.33.

m.p.=110° C. (decomposition).

IR (KBr): ν=3368, 3228, 2931, 1644, 1610, 1589, 1572, 1490, 1426, 1350,1172, 1043, 956, 929, 772 cm⁻¹.

¹H NMR (300 MHz, MeOD): δ=1.90-1.94 (m, 1H, H₁₀), 2.05-2.11 (m, 2H, H₁₀,H₁₃), 2.24 (t, J=6.2 Hz, 2H, H₁₄), 2.50 (dd, J=17.5 Hz, J=4.2 Hz, 1H,H₁₃), 2.69-2.73 (m, 1H, H₇), 2.73 (s, 3H, OMs), 2.85 (d, J=17.7 Hz, 1H,H₆), 3.02 (dd, J=17.7 Hz, J=5.5 Hz, 1H, H₆), 3.27-3.31 (m, 1H, H₁₁),4.10 (t, J=6.4 Hz, 2H, H₁₅), 5.67 (d, J=4.9 Hz, 1H, H₈), 7.28 (dd, J=9.0Hz, J=1.9 Hz, 1H, H₂), 7.65 (d, J=1.9 Hz, 1H, H₄), 8.02 (d, J=9.0 Hz,1H, H₁).

¹³C NMR (75 MHz, MeOD): δ=27.9 (C₁₁), 29.1 (C₇), 29.6 (C₁₀), 34.3 (C₁₃),36.9 (C₆), 37.6 (OMs), 39.6 (C₁₄), 69.7 (C₁₅), 115.3 (C_(11a) orC_(12a)), 116.5 (C_(11a) or C_(12a)), 123.2 (C₄), 125.5 (C₁), 126.1(C₂), 128.9 (C₈), 133.8 (C₃), 137.7 (C₉), 144.4 (C_(4a) or C₁₂), 153.1(C_(4a) or C₁₂), 156.4 (C_(5a)).

MS (ESI+): m/z (%): 393.27 (100) [M+H]⁺, 395.13 (40).

IC₅₀ rh-AChE: 8.50±1.10 nM.

IC₅₀ rh-BuChE: 415±97 nM.

EXAMPLE 153-Chloro-9-(2-hydrazinoethyl)-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinolin-12-amine Ditrifluoroacetic Acid (HUP 14)

To a partially soluble suspension of iodinated compound (HUP 7) (7.1 mg,0.017 mmol) in MeCN (2 mL) was added hydrazine monohydrate solution (8.2μL, 0.169 mmol), and the mixture was heated to 55° C. for 13 h. Thereaction mixture was concentrated to dryness then purified bypreparative HPLC (System A) and freeze dried to afford thedi-trifluoroacetate salt of the desired Huprine (HUP 14) as an off whitesolid (1.2 mg, 13%).

Rf (free base, AcOEt/MeOH 8/2, v/v)=0.43.

MS (ESI+): m/z (%): 329.33 (100) [M+H]⁺, 331.27 (35).

IC₅₀ rh-AChE: 9.5±2.7 nM.

IC₅₀ rh-BuChE: 668±110 nM.

EXAMPLE 163-Chloro-9-[2-(hydroxyamino)ethyl]-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinolin-12-amine Ditrifluoroacetic Acid (HUP 15)

A solution of di-protected compound (HUP 16) (78 mg, 0.147 mmol) inanhydrous DCM (2 mL) was treated at 0° C. with trifluoroacetic acid (1mL, 13.5 mmol). The solution was then stirred at r.t. 68 h. The reactionmixture was concentrated to dryness then purified by preparative HPLC(System A) to afford the desired Huprine (HUP 15) as a pale yellow solid(37 mg, 45%).

m.p.=130° C. (decomposition).

¹H NMR (300 MHz, MeOD): δ=1.94-2.16 (m, 3H, H₁₀, H₁₃), 2.24-2.37 (m, 2H,H₁₄), 2.60 (dd, J=17.6 Hz, J=4.4 Hz, 1H, H₁₃), 2.84-2.88 (m, 1H, H₇),2.91 (d, J=18.1 Hz, 1H, H₆), 3.19-3.28 (m, 3H, H₆, H₁₅), 3.40-3.45 (m,1H, H₁₁), 5.75 (d, J=4.7 Hz, 1H, H₈), 7.56 (dd, J=9.0 Hz, J=2.1 Hz, 1H,H₂), 7.73 (d, J=2.1 Hz, 1H, H₄), 8.34 (d, J=9.0 Hz, 1H, H₁).

¹³C NMR (75 MHz, MeOD): δ=27.3 (C₁₁), 28.1 (C₇), 28.9 (C₁₀), 32.1 (C₁₄),34.1 (C₁₃), 35.5 (C₆), 50.3 (C₁₅), 115.1 (C_(11a) or C_(12a)), 115.4(C_(11a) or C_(12a)), 119.3 (C₄), 126.4 (C₁), 127.7 (C₂), 128.1 (C₈),133.9 (C₃), 139.6 (C₉), 140.5 (C_(4a) or C₁₂), 152.9 (C_(4a) or C₁₂),156.8 (C_(5a)).

MS (ESI+): m/z (%): 330.26 (100) [M+H]⁺, 332.19 (36).

IC₅₀ rh-AChE: 18.5±2.2 nM.

IC₅₀ rh-BuChE: 43% at 1 μM.

EXAMPLE 17Tert-butyl[2-(12-amino-3-chloro-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinolin-9-yl)ethyl][(tert-butoxycarbonyl)oxy]carbamate (HUP16)

A solution of tert-butyl-N-(tert-butoxycarbonyl)-carbamate (140 mg, 0.6mmol) in anhydrous DMF (1.3 mL) was treated with sodium hydride (60% inoil, 26 mg, 0.65 mmol). The reaction mixture was stirred 40 min at r.t.and treated with a solution of mesylate (HUP 13) (157 mg, 0.4 mmol) inanhydrous DMF (2 mL). The reaction mixture was stirred at r.t. for 120h, then at 60° C. for 5 h. The mixture was then diluted with water (50mL) and extracted with AcOEt (3×30 mL). The combined organic layers werewashed with brine (50 mL), then water (50 mL), dried with Na₂SO₄ andconcentrated under reduced pressure to afford a yellow solid (313 mg).Purification by flash chromatography (AcOEt/MeOH 10/0 to 8/2, v/v)afforded the desired Huprine (HUP 16) as a white solid (98 mg, 46%).

Rf (AcOEt/MeOH 8/2, v/v)=0.50.

m.p.=114° C. (decomposition).

¹H NMR (300 MHz, CDCl₃): δ=1.41 (s, 9H, N-Boc or O-Boc), 1.46 (s, 9H,N-Boc or O-Boc), 1.84-2.02 (m, 3H, H₁₀, H₁₃), 2.10-2.22 (m, 2H, H₁₄),2.52 (dd, J=17.1 Hz, J=3.4 Hz, 1H, H₁₃), 2.67-2.71 (m, 1H, H₇), 2.89 (d,J=17.5 Hz, 1H, H₆), 3.06 (dd, J=17.6 Hz, J=5.6 Hz, 1H, H₆), 3.14-3.18(m, 1H, H₁₁), 3.66-3.88 (m, 2H, H₁₅), 5.03 (brs, 2H, NH₂), 5.56 (d,J=5.1 Hz, 1H, H₈), 7.21 (dd, J=9.0 Hz, J=1.9 Hz, 1H, H₂), 7.67 (d, J=9.0Hz, 1H, H₁), 7.77 (d, J=1.9 Hz, 1H, H₄).

¹³C NMR (75 MHz, CDCl₃): δ=27.4 (C₁₁), 27.6 (N-Boc or O-Boc), 28.1(N-Boc or O-Boc), 28.2 (C₇), 28.9 (C₁₀), 33.8 (C₁₃), 34.8 (C₁₄), 39.4(C₆), 68.1 (C₁₅), 82.3 (C-Me₃ of N-Boc), 84.9 (C-Me₃ of O-Boc), 115.1(C_(11a) or C_(12a)), 115.8 (C_(11a) or C_(12a)), 122.0 (C₁), 124.6(C₂), 126.9 (C₄), 127.0 (C₈), 132.9 (C₃), 134.6 (C₉), 146.5 (C_(4a) orC₁₂), 147.0 (C_(4a) or C₁₂), 152.2 (C═O of N-Boc), 154.8 (C═O of O-Boc),158.3 (C_(5a)).

MS (ESI+): m/z (%): 530.20 (100) [M+H]⁺, 532.20 (39).

IC₅₀ rh-AChE: 14.8±3.2 nM.

IC₅₀ rh-BuChE: 421±72 nM.

EXAMPLE 182-(12-Amino-3-chloro-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinolin-9-yl)ethylCarbamate Trifluoroacetic Acid (HUP 17)

To a partially soluble suspension of alcohol (HUP 2) (94.4 mg, 0.3 mmol)in MeCN (5 mL) was added dropwise a solution of triphosgene (178 mg, 0.6mmol) in MeCN (5 mL). The reaction mixture was stirred 20 min at 65° C.then at r.t. for 100 min, then the excess of triphosgene was quenched bybubbling ammoniac gas into the reaction mixture which led to theformation of the carbamate. The reaction mixture was concentrated todryness then purified by preparative HPLC (System A) and freeze dried toafford the trifluoroacetate salt of the desired Huprine (HUP 17) as abrown solid (82.6 mg, 58%).

m.p.=118° C. (decomposition).

¹H NMR (300 MHz, MeOD): δ=1.93-1.97 (m, 1H, H₁₀), 2.03-2.09 (m, 2H, H₁₀,H₁₃), 2.18 (t, J=6.5 Hz, 2H, H₁₄), 2.55 (dd, J=13.6 Hz, J=3.8 Hz, 1H,H₁₃), 2.78-2.82 (m, 1H, H₇), 2.87 (d, J=18.3 Hz, 1H, H₆), 3.20 (dd,J=17.9 Hz, J=5.3 Hz, 1H, H₆), 3.80-3.84 (m, 1H, H₁₁), 3.87-4.00 (m, 2H,H₁₅), 5.66 (d, J=5.1 Hz, 1H, H₈), 7.55 (dd, J=9.0 Hz, J=1.7 Hz, 1H, H₂),7.72 (d, J=1.7 Hz, 1H, H₄), 8.33 (d, J=9.0 Hz, 1H, H₁).

¹³C NMR (75 MHz, MeOD): δ=27.5 (C₁₁), 28.2 (C₇), 29.1 (C₁₀), 34.1 (C₁₃),35.8 (C₆), 37.8 (C₁₄), 63.6 (C₁₅), 115.3 (C_(11a) or C_(12a)), 115.4(C_(11a) or C_(12a)), 119.3 (C₄), 126.4 (C₁), 127.3 (C₂), 127.6 (C₈),135.2 (C₃), 139.6 (C₉), 140.4 (C_(4a) or C₁₂), 152.9 (C_(4a) or C₁₂),156.8 (C═O), 159.7 (C_(5a)).

MS (ESI+): m/z (%): 358.27 (100) [M+H]⁺, 360.20 (34).

IC₅₀ rh-AChE: 18.5±2.2 nM.

IC₅₀ rh-BuChE: 413±40 nM.

EXAMPLE 192-(12-Amino-3-chloro-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinolin-9-yl)ethylAcrylate (HUP 18)

To a cooled to 0° C. solution of alcohol (HUP 2) (20 mg, 63.5 μmol) andtriethylamine (27 μL, 200 μmol) in THF (1 mL) was added dropwiseacryloyl chloride (16 μL, 200 μmol). A white precipitate appeared: 0.5mL THF was added. The mixture was stirred 1 h at r.t. then concentratedto dryness (additionnal 0.5 mL THF was added at 45 min). Purification byflash chromatography (AcOEt/EtOH/NEt₃ 100/0/0 to 84/14.4/1.6, v/v)afforded the desired Huprine (HUP 18) as a pale yellow solid (7.9 mg,34%).

Rf (AcOEt/MeOH 8/2, v/v)=0.40.

¹H NMR (300 MHz, CDCl₃): δ=1.90-2.03 (m, 3H, H₁₀, H₁₀, H₁₃), 2.18 (t,J=6.8 Hz, 2H, H₁₄), 2.50 (dd, J=17.1 Hz, J=4.9 Hz, 1H, H₁₃), 2.73-2.77(m, 1H, H₇), 2.95 (d, J=17.7 Hz, 1H, H₆), 3.12 (dd, J=18.1 Hz, J=5.8 Hz,1H, H₆), 3.16-3.21 (m, 1H, H₁₁), 4.08 (q, J=5.5 Hz, 2H, H₁₅), 5.02 (brs,2H, NH₂), 5.61 (d, J=5.1 Hz, 1H, H₈), 5.64 (dd, J=17.1 Hz, J=1.5 Hz, 1H,H₁₈), 5.86 (dd, J=17.3 Hz, J=10.4 Hz, 1H, H₁₈), 6.15 (dd, J=17.1 Hz,J=1.5 Hz, 1H, H₁₈), 7.28 (dd, J=9.0 Hz, J=1.7 Hz, 1H, H₂), 7.67 (d,J=9.0 Hz, 1H, H₁), 7.85 (d, J=2.1 Hz, 1H, H₄).

¹³C NMR (75 MHz, CDCl₃): δ=27.5 (C₁₁), 28.3 (C₇), 29.0 (C₁₀), 33.6(C₁₃), 36.5 (C₁₄), 39.1 (C₆), 62.5 (C₁₅), 115.0 (C_(11a) or C_(12a)),115.8 (C_(11a) or C_(12a)), 122.0 (C₁), 124.9 (C₂), 127.2 (C₄), 127.7(C₈), 128.2 (C₁₇), 130.7 (C₁₈), 132.3 (C₃), 139.9 (C₉), 141.2 (C_(4a) orC₁₂), 146.6 (C_(4a) or C₁₂), 157.9 (C_(5a)), 166.1 (C₁₆).

MS (ESI+): m/z (%): 369.05 (100) [M+H]⁺, 317.11 (33).

IC₅₀ rh-AChE: 20.4±4.6 nM.

IC₅₀ rh-BuChE: 207±16 nM.

IC₅₀ erythrocyte h-AChE: 129 nM.

EXAMPLE 202-(12-Amino-3-chloro-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinolin-9-yl)-N,N-dimethylacetamideTrifluoroacetic Acid (HUP 19)

A suspension of acid (HUP 11) (99 mg, 0.27 mmol) in DMF (1 mL) and SOCl₂solution (0.2 mL, 2.74 mmol) was heated at 75° C. for 1 h30. Thereaction mixture was then cooled to r.t. and carefully hydrolyzed withsaturated aqueous K₂CO₃ solution (6 mL): a red precipitate appeared;then 1 M aqueous HCl solution (3 mL). The mixture was extracted withAcOEt (2×10 mL) then with DCM (2×20 mL). The combined organic layerswere washed with water (2×20 mL), dried with MgSO₄ and concentratedunder reduced pressure to afford brown oil. This residue wasrecrystallized in AcOEt/Et2O to afford the desired Huprine as a yellowsolid (69 mg, 74%). Purification by preparative HPLC (System A) andfreeze drying afforded the trifluoroacetate salt of the desired Huprine(HUP 19) as a pale yellow solid (71.3 mg, 62%).

Rf (free base, AcOEt)=0.66.

m.p. (free base)=217-218° C.

IR (free base, KBr): ν=3342, 3236, 2933, 1713, 1657, 1588, 1468, 1415,1375, 1229, 1155, 1084, 933 cm⁻¹.

¹H NMR (300 MHz, MeOD): δ=1.94-2.10 (m, 3H, H₁₀, H₁₃), 2.50 (dd, 1H,H₁₃, J=17.3 Hz, J=4.1 Hz), 2.80 (s, 1H, NMe), 2.90 (s, 1H, NMe),2.85-2.93 (m, 2H, H₇, H₆), 3.01 (s, 2H, H₁₄), 3.23 (dd, J=18.1 Hz, J=5.6Hz, 1H, H₆), 3.98-4.02 (m, 1H, H₁₁), 5.66 (d, J=5.1 Hz, 1H, H₈), 7.58(dd, J=9.2 Hz, J=2.1 Hz, 1H, H₂), 7.73 (d, J=2.1 Hz, 1H, H₄), 8.35 (d,J=9.2 Hz, 1H, H₁).

¹³C NMR (75 MHz, MeOD): δ=27.5 (C₁₁), 28.3 (C₇), 29.0 (C₁₀), 34.3 (C₁₃),35.7 (C₆), 35.8 (NMe), 38.1 (NMe), 43.0 (C₁₄), 115.3 (C_(11a) orC_(12a)), 115.4 (C_(11a) or C_(12a)), 119.2 (C₄), 126.4 (C₁), 127.7(C₂), 128.2 (C₈), 133.3 (C₃), 140.0 (C₉), 140.5 (C_(4a) or C₁₂), 152.9(C_(4a) or C₁₂), 156.9 (C_(5a)), 173.2 (C₁₅).

MS (ESI+): m/z (%): 356.28 (100) [M+H]⁺, 358.20 (34).

HPLC: tr=14.7 (purity 84%)

IC₅₀ rh-AChE: 26.3±1.7 nM.

IC₅₀ rh-BuChE: 2760 nM.

EXAMPLE 212-(12-Amino-3-chloro-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinolin-9-yl)acetamideTrifluoroacetic Acid (HUP 20)

To a partially soluble suspension of ester (HUP 1) (178 mg, 0.5 mmol)and sodium cyanide (25 mg, 0.25 mmol) in absolute EtOH (2 mL) wasbubbled gaseous ammoniac for 2 min. The reaction mixture was refluxedfor 6 days then the solvents were concentrated under reduced pressure todryness. Aqueous ammonia solution (28-30% in water) was added and thesuspension stirred for 2 days at r.t. The reaction mixture wasconcentrated to dryness then purified by preparative HPLC (System A) andfreeze dried to afford the trifluoroacetate salt of the desired Huprine(HUP 20) as a white solid (15.3 mg, 7%).

m.p.=126° C. (decomposition).

¹H NMR (300 MHz, MeOD): δ=1.93-2.00 (m, 1H, H₁₀), 2.06-2.16 (m, 2H, H₁₀,H₁₃), 2.55 (dd, 1H, J=17.7 Hz, J=4.1 Hz, H₁₃), 2.78-2.81 (m, 2H, H₁₄),2.83-2.87 (m, 1H, H₇), 2.91 (d, J=17.9 Hz, 1H, H₆), 3.22 (dd, J=17.9 Hz,J=5.5 Hz, 1H, H₆), 3.38-3.42 (m, 1H, H₁₁), 5.76 (d, J=5.3 Hz, 1H, H₈),7.58 (dd, J=9.1 Hz, J=2.1 Hz, 1H, H₂), 7.72 (d, J=2.1 Hz, 1H, H₄), 8.34(d, J=9.1 Hz, 1H, H₁).

¹³C NMR (75 MHz, MeOD): δ=27.4 (C₁₁), 28.3 (C₇), 28.9 (C₁₀), 34.0 (C₁₃),35.6 (C₆), 45.0 (C₁₄), 115.3 (C_(11a) or C_(12a)), 115.4 (C_(11a) orC_(12a)), 119.2 (C₄), 126.4 (C₁), 127.7 (C₂), 128.9 (C₈), 133.6 (C₃),139.7 (C₉), 140.5 (C_(4a) or C₁₂), 152.9 (C_(4a) or C₁₂), 156.9(C_(5a)), 176.4 (C₁₅).

MS (ESI+): m/z (%): 328.33 (100) [M+H]⁺, 330.20 (33).

IC₅₀ rh-AChE: 29.3±3.7 nM.

IC₅₀ rh-BuChE: <1% at 1 μM.

EXAMPLE 223-Chloro-9-[2-(dimethylamino)ethyl]-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinolin-12-amine Ditrifluoroacetic Acid (HUP 21)

A partially soluble suspension of iodinated compound (HUP 7) (61 mg,0.14 mmol), dimethylamine hydrochloride (147 mg, 1.80 mmol) and sodiumbicarbonate (151 mg, 1.8 mmol) AcOEt/MeCN mixture (10 mL/2 mL) wasstirred 13 h at reflux. The reaction mixture was concentrated to drynessthen purified by preparative HPLC (System A) and freeze dried to affordthe di-trifluoroacetate salt of the desired Huprine (HUP 21) as a whitesolid (11.1 mg, 14%).

Rf (AcOEt/MeOH 8/2, v/v)=0.58.

m.p.=118° C. (decomposition).

IR (KBr): ν=3354, 3174, 2940, 1673, 1591, 1470, 1421, 1201, 1126, 834,721 cm⁻¹.

¹H NMR (300 MHz, MeOD): δ=2.00-2.08 (m, 3H, H₁₀, H₁₃), 2.28-2.32 (m, 2H,H₁₄), 2.60 (dd, J=17.0 Hz, J=3.9 Hz, 1H, H₁₃), 2.82 (s, 6H, Me₂N),2.82-2.93 (m, 2H, H₇, H₆), 3.12 (t, J=8.1 Hz, 2H, H₁₅), 3.19-3.23 (m,1H, H₆), 3.42-3.46 (m, 1H, H₁₁), 5.77 (d, J=5.1 Hz, 1H, H₈), 7.61 (dd,J=9.0 Hz, J=1.9 Hz, 1H, H₂), 7.75 (d, J=1.5 Hz, 1H, H₄), 8.36 (d, J=9.0Hz, 1H, H₁).

¹³C NMR (75 MHz, MeOD): δ=27.3 (C₁₁), 28.2 (C₇), 28.9 (C₁₀), 33.0 (C₁₄),34.3 (C₁₃), 35.6 (C₆), 43.5 (2C, Me₂N), 57.1 (C₁₅), 115.1 (C_(11a) orC_(12a)), 115.5 (C_(11a) or C_(12a)), 119.3 (C₄), 126.4 (C₁), 127.8(C₂), 128.2 (C₈), 133.9 (C₃), 139.7 (C₉), 140.6 (C_(4a) or C₁₂), 152.9(C_(4a) or C₁₂), 156.9 (C_(5a)).

MS (ESI+): m/z (%): 342.33 (100) [M+H]⁺, 344.27 (37).

IC₅₀ rh-AChE: 97±10 nM.

IC₅₀ rh-BuChE: 2910 nM.

EXAMPLE 23 Methyl1-[2-(12-amino-3-chloro-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinolin-9-yl)ethyl]-1H-1,2,3-triazole-4-carboxylate (HUP22)

A solution of azide (HUP 12) (64 mg, 188 μmol), methyl propionate (18μL, 200 μmol) and copper iodide (4.4 mg, 22.7 μmol) in MeCN (4 mL) wasstirred 25 h at r.t. with light protection. The reaction mixture wasconcentrated to dryness then purified by flash chromatography(AcOEt/MeOH 10/0 to 9/1, v/v) to afford the desired Huprine (HUP 22) asa yellow solid (47.5 mg, 60%).

Rf (AcOEt/MeOH 9/1, v/v)=0.10.

m.p.=126° C. (decomposition).

IR (KBr): ν=3365, 2927, 1732, 1646, 1609, 1572, 1490, 1435, 1373, 1218,1109, 929, 770 cm⁻¹.

¹H NMR (300 MHz, MeOD): δ=1.88-1.99 (m, 2H, H₁₀), 2.04-2.09 (m, 1H,H₁₃), 2.45-2.52 (m, 3H, H₁₄, H₁₃), 2.65-2.69 (m, 1H, H₇), 2.66 (d,J=17.5 Hz, 1H, H₆), 3.00 (dd, J=17.3 Hz, J=5.4 Hz, 1H, H₆), 3.29-3.33(m, 1H, H₁₁), 3.84 (s, 3H, H₁₉), 4.38 (td, J=2.3 Hz, J=6.8 Hz, 2H, H₁₅),5.49 (d, J=5.1 Hz, 1H, H₈), 7.31 (dd, J=8.9 Hz, J=1.7 Hz, 1H, H₂), 7.67(d, J=1.7 Hz, 1H, H₄), 8.05 (s, 1H, H₁₆), 8.06 (d, J=8.9 Hz, 1H, H₁).

¹³C NMR (75 MHz, MeOD): δ=28.1 (C₁₁), 29.5 (C₇), 29.9 (C₁₀), 34.2 (C₁₃),38.2 (C₁₄), 39.5 (C₆), 49.9 (C₁₅), 52.6 (C₁₉), 115.2 (C_(11a) orC_(12a)), 117.0 (C_(11a) or C_(12a)), 125.0 (C₁), 125.3 (C₂), 125.8(C₄), 129.3 (C₁₆), 129.6 (C₈), 133.6 (C₃), 136.1 (C₉), 140.0 (C₁₇),147.3 (C_(4a)), 150.1 (C₁₂), 158.3 (C_(5a)), 162.2 (C₁₈).

MS (ESI+): m/z (%): 424.20 (100) [M+H]⁺, 426.13 (33).

IC₅₀ rh-AChE: 130±15 nM.

IC₅₀ rh-BuChE: 42% at 1 μM.

EXAMPLE 24{1-[2-(12-Amino-3-chloro-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinolin-9-yl)ethyl]-1H-1,2,3-triazol-4-yl}methanolTrifluoroacetic Acid (HUP 23)

To a cooled to 0° C. stirred suspension of LiAlH₄ (11 mg, 275 μmol) inTHF (500 μL) was added dropwise a solution of triazole (HUP 22) (12.7mg, 30 μmol) in THF (1 mL). The solution was stirred 30 min (0° C. tor.t.) then quenched carefully at 0° C. by the addition of water (50 μL),then 5 M NaOH solution (50 μL), then water (150 μL). The reactionmixture was stirred 10 min (0° C. to r.t.) concentrated to dryness. Theresidue was purified by preparative HPLC (System A) and freeze dried toafford the trifluoroacetate salt of the desired Huprine (HUP 23) as awhite solid (62.2 mg, 57%).

m.p.=119° C. (decomposition).

¹H NMR (300 MHz, MeOD): δ=1.86-2.02 (m, 2H, H₁₀), 2.04-2.12 (m, 1H,H₁₃), 2.42-2.55 (m, 3H, H₁₄, H₁₃), 2.58-2.65 (d, J=17.5 Hz, 1H, H₆),2.66-2.70 (m, 1H, H₇), 3.10 (dd, J=17.8 Hz, J=5.5 Hz, 1H, H₆), 3.34-3.38(m, 1H, H₁₁), 4.33 (t, J=5.8 Hz, 2H, H₁₅), 4.50 (s, 1H, H₁₈), 5.43 (d,J=5.1 Hz, 1H, H₈), 7.59 (s, 1H, H₁₆), 7.61 (dd, J=8.9 Hz, J=1.7 Hz, 1H,H₂), 7.77 (d, J=1.7 Hz, 1H, H₄), 8.36 (d, J=8.9 Hz, 1H, H₁).

¹³C NMR (75 MHz, MeOD): δ=27.4 (C₁₁), 28.0 (C₇), 28.9 (C₁₀), 33.2 (C₁₃),35.4 (C₆), 38.2 (C₁₄), 48.5 (C₁₅), 56.4 (C₁₈), 115.2 (C_(11a) orC_(12a)), 115.5 (C_(11a) or C_(12a)), 119.5 (C₄), 123.6 (CH₁₆), 126.4(C₁), 127.7 (C₂), 128.6 (C₈), 134.2 (C₃), 139.7 (C₉), 140.4 (C₁₇), 148.9(C_(4a)), 152.7 (C₁₂), 156.8 (C_(5a)).

MS (ESI+): m/z (%): 396.27 (100) [M+H]⁺, 114.73 (59), 398.20 (32).

HPLC: tr=13.7 (purity 99%).

IC₅₀ rh-AChE: 210±28 nM.

IC₅₀ rh-BuChE: 18% at 1 μM.

EXAMPLE 259-(2-Aminoethyl)-3-chloro-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinolin-12-amineDitrifluoroacetic Acid (HUP 24)

A solution of azide (HUP 12) (68 mg, 0.2 mmol) and triphenylphosphine(53 mg, 0.2 mmol) in THF (1 mL) was stirred 2 h at 0° C. and 1 h (0° C.to r.t.). Water (10 μL) was then added at 0° C. and the mixture wasstirred at r.t. for 13 h. The reaction mixture was concentrated todryness then purified by preparative HPLC (System A) and freeze dried toafford the trifluoroacetate salt of the desired Huprine (HUP 24) as awhite solid (65 mg, 60%).

m.p.=150° C. (decomposition).

¹H NMR (300 MHz, MeOD): δ=1.95-2.04 (m, 2H, H₁₀, H₁₃), 2.10-2.15 (m, 1H,H₁₀), 2.22 (t, J=7.4 Hz, 2H, H₁₃), 2.60 (dd, J=17.7 Hz, J=3.8 Hz, 1H,H₁₃), 2.86-2.97 (m, 4H, H₇, H₆, H₁₅), 2.24 (dd, J=17.7 Hz, J=5.6 Hz, 1H,H₆), 3.41-3.45 (m, 1H, H₁₁), 5.74 (d, J=4.9 Hz, 1H, H₈), 7.57 (dd, J=9.0Hz, J=1.9 Hz, 1H, H₂), 7.74 (d, J=1.9 Hz, 1H, H₄), 8.35 (d, J=9.0 Hz,1H, H₁).

¹³C NMR (75 MHz, MeOD): δ=27.3 (C₁₁), 28.1 (C₇), 28.9 (C₁₀), 34.1 (C₁₃),35.6 (C₆), 36.0 (C₁₄), 38.8 (C₁₅), 115.1 (C_(11a) or C_(12a)), 115.4(C_(11a) or C_(12a)), 119.3 (C₄), 126.4 (C₁), 127.7 (C₂), 128.1 (C₈),134.1 (C₃), 139.6 (C₉), 140.5 (C_(4a) or C₁₂), 152.9 (C_(4a) or C₁₂),156.8 (C_(5a)).

MS (ESI+): m/z (%): 314.30 (100) [M+H]⁺, 316.23 (35), 178.05 (31).

IC₅₀ rh-AChE: 244±62 nM.

IC₅₀ rh-BuChE: 991 nM.

EXAMPLE 262-(12-Amino-3-chloro-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinolin-9-yl)-N,N,N-trimethylethanaminiumDitrifluoroacetic Acid (HUP 25)

To a partially soluble suspension of iodinated compound (HUP 7) (71 mg,0.167 mmol) in MeCN (2 mL) was added a solution of 1 M trimethylamine inTHF (1.7 mL, 1.67 mmol), and the mixture was heated to 55° C. for 13 h.The reaction mixture was concentrated to dryness then purified bypreparative HPLC (System A) and freeze dried to afford thedi-trifluoroacetate salt of the desired Huprine (HUP 25) as a whitesolid (26.3 mg, 27%) along with alkene (HUP 3) (37.7 mg, 55%) asβ-elimination byproduct.

Rf (AcOEt/MeOH 8/2, v/v)=0.67.

m.p.=188° C. (decomposition).

¹H NMR (300 MHz, MeOD): δ=2.00-2.11 (m, 3H, H₁₀, H₁₃), 2.39 (t, J=6.9Hz, 2H, H₁₄), 2.60 (dd, J=17.1 Hz, J=3.8 Hz, 1H, H₁₃), 2.85-2.94 (m, 2H,H₇, H₆), 3.07 (s, 9H, Me₃N⁺), 3.18-3.24 (m, 1H, H₆), 3.29-3.33 (m, 2H,H₁₅), 3.43-3.46 (m, 1H, H₁₁), 5.80 (d, J=4.7 Hz, 1H, H₈), 7.61 (dd,J=9.0 Hz, J=1.9 Hz, 1H, H₂), 7.76 (d, J=1.9 Hz, 1H, H₄), 8.37 (d, J=9.0Hz, 1H, H₁).

¹³C NMR (75 MHz, MeOD): δ=27.3 (C₁₁), 28.2 (C₇), 28.9 (C₁₀), 31.1 (C₁₄),34.5 (C₁₃), 35.5 (C₆), 53.4 (Me₃N⁺), 53.5 (Me₃N⁺), 53.6 (Me₃N⁺), 66.0(C₁₅), 115.1 (C_(11a) or C_(12a)), 115.4 (C_(11a) or C_(12a)), 119.3(C₄), 126.5 (C₁), 127.8 (C₂), 128.5 (C₈), 133.5 (C₃), 139.7 (C₉), 140.6(C_(4a) or C₁₂), 152.8 (C_(4a) or C₁₂), 156.9 (C_(5a)).

MS (ESI+): m/z (%): 356.21 (100) [M+H]⁺, 178.85 (51) [M+2H]²⁺, 358.20(33).

IC₅₀ rh-AChE: 262±22 nM.

IC₅₀ rh-BuChE: <1% at 1 μM.

EXAMPLE 27 Dimethyl[2-(12-Amino-3-chloro-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinolin-9-yl)ethyl]malonate (HUP 26)

To a solution of sodium dimethylmalonate [prepared from sodium (106 mg,4.6 mmol) and dimethyl malonate (686 μL, 6.0 mmol) in dry THF (4 mL) letfor 1 h30 in ultrasounds bath] was added a solution of mesyl compoundmesylate (HUP 13) (1.572 g, 4.0 mmol) in dry THF (14 mL). The mixturewas stirred at reflux temperature for 5 days. The cooled reactionmixture was then hydrolyzed with water (5 mL) and concentrated todryness. Water (40 mL) was then added and the product extracted withAcOEt (3×50 mL). The combined organic layers were dried with Na₂SO₄ andconcentrated under reduced pressure to afford a brown residue (1.877 g).Purification by flash chromatography (petroleum ether/AcOEt/MeOH 10/0/0to 0/9/1, v/v/v) afforded the desired Huprine (HUP 26) as a white solid(1.098 g, 64%).

Rf (AcOEt/MeOH 8/2, v/v)=0.31.

¹H NMR (300 MHz, CDCl₃): δ=1.78-1.83 (m, 4H, H₁₄, H₁₅), 1.87-1.97 (m,3H, H₁₀, H₁₀, H₁₃), 2.39 (dd, J=16.6 Hz, J=4.0 Hz, 1H, H₁₃), 2.67-2.71(m, 1H, H₇), 2.89 (d, J=17.5 Hz, 1H, H₆), 3.01-3.10 (m, 2H, H₆, H₁₆),3.15-3.17 (m, 1H, H₁₁), 3.51 (s, 3H, OMe), 3.63 (s, 3H, OMe), 4.97 (brs,NH₂), 5.49 (d, J=5.1 Hz, 1H, H₈), 7.19 (dd, J=9.0 Hz, J=2.1 Hz, 1H, H₂),7.63 (d, J=9.0 Hz, 1H, H₁), 7.79 (d, J=2.1 Hz, 1H, H₄).

¹³C NMR (75 MHz, CDCl₃): δ=26.5 (C₁₅), 27.4 (C₁₁), 28.3 (C₇), 29.1(C₁₀), 33.4 (C₁₃), 34.7 (C₁₄), 39.8 (C₆), 50.4 (C₁₆), 52.3 (OMe), 52.4(OMe), 115.0 (C_(11a) or C_(12a)), 115.9 (C_(11a) or C_(12a)), 121.9(C₁), 124.4 (C₂), 126.5 (C₈), 127.5 (C₄), 134.1 (C₃), 134.2 (C₉), 145.9(C_(4a) or C₁₂), 147.5 (C_(4a) or C₁₂), 158.9 (C_(5a)), 169.7 (C═O),169.8 (C═O).

MS (ESI+): m/z (%): 429.40 (100) [M+H]⁺, 431.27 (38), 856.80 (35),858.60 (31).

EXAMPLE 28Diethyl[2-(12-Amino-3-chloro-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinolin-9-yl)ethyl]malonate (HUP 27)

To a solution of sodium diethylmalonate [prepared from sodium (13.8 mg,0.6 mmol) and diethyl malonate (128 μL, 0.84 mmol) in absolute EtOH (0.5mL)] was added a solution of mesylate (HUP 13) (166 mg, 0.42 mmol) inabsolute EtOH (1.5 mL). The mixture was stirred at reflux for 44 h. Thecooled reaction mixture was then hydrolyzed with water (2 mL) andconcentrated to dryness. Water (15 mL) was then added and the productextracted with AcOEt (3×15 mL). The combined organic layers were driedwith MgSO₄ and concentrated under reduced pressure to afford a brownresidue (209 mg). Purification by flash chromatography (AcOEt/MeOH 10/0to 9/1, v/v) afforded the desired Huprine) HUP 27) as an almost whitesolid (112 mg, 58%).

Rf (AcOEt/MeOH 8/2, v/v)=0.61.

¹H NMR (300 MHz, MeOD): δ=1.04 (t, J=7.0 Hz, 3H, CH₃ of OEt), 1.19 (t,J=7.0 Hz, 3H, CH₃ of OEt), 1.70-1.77 (m, 2H, H₁₅), 1.80-1.86 (m, 2H,H₁₄), 1.92.-2.02 (m, 2H, H₁₀, H₁₃), 2.06-2.09 (m, 1H, H₁₀), 2.38 (d,J=17.1 Hz, 1H, H₁₃), 2.65-2.70 (m, 1H, H₇), 2.79-2.89 (m, 2H, H₆, H₁₆),3.04 (dd, J=17.1 Hz, J=5.3 Hz, 1H, H₆), 3.28-3.33 (m, 1H, H₁₁),3.80-3.88 (m, 2H, CH₂ of OEt), 4.09 (q, J=7.1 Hz, 2H, CH₂ of OEt), 5.51(d, J=4.3 Hz, 1H, H₈), 7.25 (dd, J=9.0 Hz, J=2.1 Hz, 1H, H₂), 7.67 (d,J=2.1 Hz, 1H, H₄), 8.02 (d, J=9.0 Hz, 1H, H₁).

¹³C NMR (75 MHz, MeOD): δ=14.3 (CH₃ of OEt), 14.5 (CH₃ of OEt), 27.4(C₁₅), 28.4 (C₁₁), 29.8 (C₇), 30.3 (C₁₀), 34.0 (C₁₃), 35.3 (C₁₄), 40.3(C₆), 51.3 (C₁₆), 62.2 (CH₂ of OEt), 62.3 (CH₂ of OEt), 115.3 (C_(11a)or C_(12a)), 117.2 (C_(11a) or C_(12a)), 124.8 (C₁), 124.9 (C₂), 126.4(C₄), 127.9 (C₈), 135.6 (C₃), 136.2 (C₉), 148.1 (C_(4a) or C₁₂), 150.0(C_(4a) or C₁₂), 159.2 (C_(5a)), 170.8 (C═O), 170.9 (C═O).

MS (ESI+): m/z (%): 457.33 (100), 195.13 (58), 251.00 (48), 459.40 (35),914.60 (27).

IC₅₀ rh-AChE: 6.09±0.42 nM.

IC₅₀ rh-BuChE: 319±2 nM.

IC₅₀ erythrocyte h-AChE: 46.4 nM.

EXAMPLE 292-[2-(12-Amino-3-chloro-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinolin-9-yl)ethyl]propane-1,3-diolTrifluoroactic Acid (HUP 28)

To a cooled (0° C.) stirred suspension of anhydrous LiAlH₄ (8.6 mg, 214mmol) in dry THF (1 mL) was added dropwise a solution of dimethylmalonate (HUP 26) (46 mg, 107 μmol) in dry THF (4 mL). The solution wasstirred 20 h (0° C. to r.t.) then quenched carefully at 0° C. by theaddition of water (50 μL), then 5 M NaOH solution (50 μL), then water(150 μL). The reaction mixture was stirred 10 min at r.t. then driedwith Na₂SO₄. The dried solution and washings (with AcOEt) were filteredand concentrated under reduced pressure to give a yellow solid (97 mg).Purification by preparative HPLC (System B) afforded thetrifluoroacetate salt of the desired Huprine (HUP 28) as a light yellowsolid (18.0 mg, 45%).

¹H NMR (300 MHz, CDCl₃): δ=1.32-1.49 (m, 3H, H₁₅, H₁₅, H₁₆), 1.84-2.12(m, 5H, H₁₀, H₁₀, H₁₃, H₁₄, H₁₄), 2.52 (d, J=16.9 Hz, 1H, H₁₃),2.80-2.85 (m, 1H, H₇), 2.86 (d, J=18.1 Hz, 1H, H₆), 3.21 (dd, J=17.9 Hz,J=3.6 Hz, 1H, H₆), 3.35-3.52 (m, 3H, H₁₁, H₁₈, H₁₈), 3.73 (t, J=6.6 Hz,1H, H₁₇), 4.25 (dd, J=30.0 Hz, J=5.9 Hz, 1H, H₁₇), 5.60-5.66 (m, 1H,H₈), 7.59 (dd, J=9.0 Hz, J=2.1 Hz, 1H, H₂), 7.73 (d, J=2.1 Hz, 1H, H₄),8.35 (d, J=9.0 Hz, 1H, H₁).

¹³C NMR (75 MHz, CDCl₃): δ=26.5 (C₁₅), 27.5 (C₁₁), 28.1 (C₇), 29.3(C₁₀), 34.0 (C₁₃), 35.6 (C₁₄), 36.0 (C₆), 40.4 (C₁₆), 63.3 (C₁₈), 68.9(C₁₇), 115.4 (C_(11a) or C_(12a)), 115.5 (C_(11a) or C_(12a)), 124.9(C₄), 124.9 (C₈), 125.8 (C₃), 126.3 (C₁), 127.7 (C₂), 138.8 (C₉), 140.5(C_(4a) or C₁₂), 153.0 (C_(4a) or C₁₂), 156.8 (C_(5a)).

MS (ESI+): m/z (%): 373.11 (100) [M+H]⁺, 374.97 (33).

IC₅₀ rh-AChE: 24.7±1.2 nM.

IC₅₀ rh-BuChE: 37% at 1 μM.

IC₅₀ erythrocyte h-AChE: 40.2 nM.

EXAMPLE 30 Methyl 4-(12-Amino-3-chloro-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinolin-9-yl)butanoate (HUP 29)

A solution of dimethyl malonate (HUP 26) (957 mg, 2.23 mmol), sodiumchloride (265 mg, 4.46 mmol) and water (80 μL, 4.40 mmol) in DMSO (2.57mL) was refluxed 7 h under argon. The cooled reaction mixture wasdiluted in AcOEt (15 mL) then partionned between water (25 mL) and AcOEt(100 mL). The organic phase was separated and the aqueous one extractedwith AcOEt (4×50 mL), DCM (2×50 mL) and again AcOEt (50 mL). Thecombined organic layers were dried with Na₂SO₄ and concentrated underreduced pressure to afford brown oil containing residual DMSO.Purification by flash chromatography (petroleum ether/AcOEt 10/0 to 0/10then AcOEt/MeOH 9.5/0.5, v/v) afforded the desired Huprine (HUP 29) asyellow crystals (356 mg, 43%).

Rf (AcOEt/MeOH 9/1, v/v)=0.31.

¹H NMR (300 MHz, CDCl₃): δ=1.51-1.60 (m, 2H, H₁₅), 1.80 (t, J=7.5 Hz,2H, H₁₄) 1.92-2.04 (m, 3H, H₁₀, H₁₀, H₁₃), 2.05-2.15 (m, 2H, H₁₆), 2.42(dd, J=16.7 Hz, J=4.1 Hz, 1H, H₁₃), 2.70-2.74 (m, 1H, H₇), 2.92 (d,J=9.7 Hz, 1H, H₆), 3.09 (dd, J=17.5 Hz, J=5.5 Hz, 1H, H₆), 3.16-3.19 (m,1H, H₁₁), 3.52 (s, 3H, OMe), 4.86 (brs, NH₂), 5.51 (d, J=4.9 Hz, 1H,H₈), 7.23 (dd, J=9.0 Hz, J=2.1 Hz, 1H, H₂), 7.62 (d, J=9.0 Hz, 1H, H₁),7.82 (d, J=2.1 Hz, 1H, H₄).

¹³C NMR (75 MHz, CDCl₃): δ=22.5 (C₁₅), 27.6 (C₁₁), 28.4 (C₇), 29.3(C₁₀), 33.1 (C₁₆), 33.6 (C₁₃), 36.5 (C₁₄), 39.9 (C₆), 51.4 (OMe), 115.3(C_(11a) or C_(12a)), 115.9 (C_(11a) or C_(12a)), 121.7 (C₁), 124.6(C₂), 125.8 (C₈), 127.6 (C₄), 134.3 (C₃), 135.0 (C₉), 145.8 (C_(4a) orC₁₂), 147.4 (C_(4a) or C₁₂), 158.8 (C_(5a)), 174.2 (C═O).

MS (ESI+): m/z (%): 371.47 (100) [M+H]⁺, 373.33 (46), 742.87 (7)[2M+2H]⁺.

IC₅₀ rh-AChE: 14.6±1.7 nM.

IC₅₀ rh-BuChE: 124±11 nM.

IC₅₀ erythrocyte h-AChE: 37.6 nM.

EXAMPLE 314-(12-Amino-3-chloro-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinolin-9-yl)butan-1-ol(HUP 30)

To a cooled (0° C.) stirred suspension of anhydrous LiAlH₄ (76 mg, 1.9mmol) in dry THF (5 mL) was added dropwise a solution of ester (HUP 29)(343 mg, 0.92 mmol) in dry THF (10 mL). The solution was stirred 40 min(0° C. to r.t.) then quenched carefully at 0° C. by the addition ofwater (0.5 mL), then 5 M NaOH solution (0.5 mL), then water (1.5 mL).The reaction mixture was stirred 10 min at r.t. then dried with Na₂SO₄.The dried solution and washings (with AcOEt) were filtered andconcentrated under reduced pressure to give a yellow solid (534 mg).Purification by flash chromatography (AcOEt/MeOH 100/0 to 92/8) affordedthe desired Huprine (HUP 30) as a pale yellow solid (yield calculated atthe next step).

Rf (AcOEt/MeOH 8/2, v/v)=0.30.

¹H NMR (300 MHz, CDCl₃): δ=1.21-1.30 (m, 4H, H₁₄, H₁₅), 1.75-1.80 (m,2H, H₁₆), 1.90-1.98 (m, 3H, H₁₀, H₁₀, H₁₃), 2.41 (dd, J=16.9 Hz, J=4.3Hz, 1H, H₁₃), 2.40-2.60 (brs, 1H, OH), 2.68-2.72 (m, 1H, H₇), 2.91 (d,J=17.5 Hz, 1H, H₆), 3.09 (dd, J=17.4 Hz, J=5.3 Hz, 1H, H₆), 3.16-3.19(m, 1H, H₁₁), 3.47 (t, J=17.4 Hz, 2H, H₁₇), 4.85 (brs, NH₂), 5.48 (d,J=5.1 Hz, 1H, H₈), 7.24 (dd, J=9.0 Hz, J=2.1 Hz, 1H, H₂), 7.61 (d, J=9.0Hz, 1H, H₁), 7.82 (d, J=2.1 Hz, 1H, H₄).

¹³C NMR (75 MHz, CDCl₃): δ=23.5 (C₁₅), 27.8 (C₁₁), 28.4 (C₇), 29.4(C₁₀), 32.1 (C₁₄), 33.8 (C₁₃), 37.0 (C₁₆), 40.1 (C₆), 62.8 (C₁₇), 115.6(C_(11a) or C₁₂), 115.9 (C_(11a) or C_(12a)), 121.5 (C₁), 124.8 (C₂),125.3 (C₈), 127.8 (C₄), 134.4 (C₃), 135.8 (C₉), 145.6 (C_(4a) or C₁₂),147.5 (C_(4a) or C₁₂), 159.0 (C_(5a)).

MS (ESI+): m/z (%): 343.40 (100) [M+H]⁺, 345.27 (35).

IC₅₀ rh-AChE: 22.4±1.5 nM.

IC₅₀ rh-BuChE: 343±43 nM.

IC₅₀ erythrocyte h-AChE: 50.1 nM.

EXAMPLE 324-(12-Amino-3-chloro-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinolin-9-yl)butylMethanesulfonate (HUP 31)

To a cooled (0° C.) stirred solution of alcohol (HUP 30) (332 mg, 0.9mmol) and triethylamine (253 μL, 1.8 mmol) in dry THF (15 mL) was addedMethane sulfonyl chloride (140 μL, 1.8 mmol) dropwise over 5 min. Thesolution was stirred 30 min (0° C. to r.t.); THF (5 mL) was added todilute the solution. The reaction mixture was then poured onto asaturated aqueous solution of Na₂CO₃ and the aqueous phase was extractedwith AcOEt (3×40 mL). The combined organic layers were dried with Na₂SO₄and concentrated under reduced pressure to give a yellow solid (730 mg).Purification by flash chromatography (AcOEt/MeOH 100/0 to 92/8) affordedthe desired Huprine (HUP 31) as a pale yellow solid (296 mg, 87% overtwo steps).

Rf (AcOEt/MeOH 9/1, v/v)=0.23.

¹H NMR (300 MHz, CDCl₃): δ=1.32-1.37 (m, 4H, H₁₄, H₁₅), 1.83-1.87 (m,2H, H₁₆), 1.95-2.02 (m, 3H, H₁₀, H₁₀, H₁₃), 2.44 (dd, J=16.7 Hz, J=4.7Hz, 1H, H₁₃), 2.74-2.78 (m, 1H, H₇), 2.86 (s, 3H, OMs), 2.94 (d, J=17.7Hz, 1H, H₆), 3.14 (dd, J=17.5 Hz, J=5.5 Hz, 1H, H₆), 3.20-3.23 (m, 1H,H₁₁), 4.00 (m, 2H, H₁₇), 4.86 (brs, NH₂), 5.54 (d, J=5.3 Hz, 1H, H₈),7.29 (dd, J=9.0 Hz, J=2.1 Hz, 1H, H₂), 7.67 (d, J=9.0 Hz, 1H, H₁), 7.85(d, J=2.1 Hz, 1H, H₄).

¹³C NMR (75 MHz, CDCl₃): δ=23.2 (C₁₅), 27.6 (C₁₁), 28.3 (C₁₄), 28.4(C₇), 29.4 (C₁₀), 33.5 (C₁₃), 36.4 (C₁₆), 37.3 (OMs), 39.9 (C₆), 70.1(C₁₇), 115.4 (C_(11a) or C_(12a)), 115.9 (C_(11a) or C_(12a)), 121.8(C₁), 124.8 (C₂), 125.8 (C₈), 127.4 (C₄), 134.6 (C₃), 135.2 (C₉), 146.1(C_(4a) or C₁₂), 147.2 (C_(4a) or C₁₂), 158.6 (C_(5a)).

MS (ESI+): m/z (%): 421.27 (100) [M+H]⁺, 423.20 (39).

IC₅₀ rh-AChE: 4.76±1.68 nM.

IC₅₀ rh-BuChE: 243±12 nM.

IC₅₀ erythrocyte h-AChE: 13.3 nM.

EXAMPLE 339-(4-Azidobutyl)-3-chloro-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinolin-12-amine(HUP 32)

A mixture of mesylate (HUP 31) (282 mg, 0.67 mmol) and sodium azide (163mg, 2.5 mmol) in dry DMF (3.5 mL) was stirred at 70° C. under argon for6 h. The cooled reaction mixture was then hydrolyzed with water (5 mL)under stirring. Water (25 mL) was then added and the product extractedwith AcOEt (3×30 mL). The combined organic layers were dried with Na₂SO₄and concentrated under reduced pressure to afford yellow oil containingresidual DMF. Purification by flash chromatography (AcOEt/MeOH 10/0 to9.5/0.5, v/v) afforded the desired Huprine (HUP 32) as a pale yellowsolid (165 mg, 68%).

Rf (AcOEt/MeOH 9/1, v/v)=0.36.

¹H NMR (300 MHz, CDCl₃): δ=1.28-1.35 (m, 4H, H₁₄, H₁₆), 1.82 (t, J=6.6Hz, 2H, H₁₄), 1.94-2.02 (m, 3H, H₁₀, H₁₀, H₁₃), 2.45 (dd, J=16.9 Hz,J=4.5 Hz, 1H, H₁₃), 2.73-2.77 (m, 1H, H₇), 2.93 (d, J=17.5 Hz, 1H, H₆),3.07-3.10 (m, 2H, H₁₇), 3.11 (dd, J=17.5 Hz, J=5.6 Hz, 1H, H₆),3.19-3.21 (m, 1H, H₁₁), 4.82 (brs, NH₂), 5.52 (d, J=5.3 Hz, 1H, H₈),7.27 (dd, J=9.0 Hz, J=2.1 Hz, 1H, H₂), 7.63 (d, J=9.0 Hz, 1H, H₁), 7.84(d, J=2.1 Hz, 1H, H₄).

¹³C NMR (75 MHz, CDCl₃): δ=24.4 (C₁₅), 27.7 (C₁₁), 28.2 (C₁₆), 28.4(C₇), 29.4 (C₁₀), 33.7 (C₁₃), 36.8 (C₁₄), 39.9 (C₆), 51.3 (C₁₇), 115.4(C_(11a) or C_(12a)), 115.9 (C_(11a) or C_(12a)), 121.6 (C₁), 124.8(C₂), 125.5 (C₈), 127.7 (C₄), 134.4 (C₃), 135.4 (C₉), 145.8 (C_(4a) orC₁₂), 147.4 (C_(4a) or C₁₂), 158.8 (C_(5a)).

MS (ESI+): m/z (%): 368.27 (100) [M+H]⁺, 370.20 (33).

IC₅₀ rh-AChE: 13.1±4.7 nM.

IC₅₀ rh-BuChE: 260±12 nM.

IC₅₀ erythrocyte h-AChE: 68.1 nM.

EXAMPLE 34 Methyl1-[4-(12-Amino-3-chloro-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinolin-9-yl)butyl]-1H-1,2,3-triazole-4-carboxylate (HUP33)

A mixture of azide (HUP 32) (74 mg, 0.20 mmol), copper iodide (7.6 mg,0.04 mmol) and methyl propionate (23 μL, 0.25 mmol) in MeCN (4 mL) wasstirred at r.t. with light protection for 23 h. The reaction mixture wasconcentrated to dryness then purified by flash chromatography(AcOEt/MeOH/[EtOH/NEt₃, 9/1] 100/0/0 to 92/4/4, v/v/v) to afford thedesired Huprine (HUP 33) as white crystals (82 mg, 91%).

Rf (AcOEt/MeOH 8/2, v/v)=0.35.

¹H NMR (300 MHz, MeOD): δ=1.22-1.26 (m, 2H, H₁₅), 1.45-1.63 (m, 2H,H₁₆), 1.85-1.94 (m, 3H, H₁₄, H₁₄, H₁₀), 1.97-2.06 (m, 2H, H₁₀, H₁₃),2.37 (dd, J=17.1 Hz, J=4.0 Hz, 1H, H₁₃), 2.68-2.71 (m, 1H, H₇), 2.82 (d,J=17.5 Hz, 1H, H₆), 3.04 (dd, J=17.5 Hz, J=5.5 Hz, 1H, H₆), 3.30-3.33(m, 1H, H₁₁), 3.91 (s, 3H, MeO), 4.15 (t, J=7.2 Hz, 2H, H₁₇), 5.54 (d,J=5.3 Hz, 1H, H₈), 7.25 (dd, J=9.0 Hz, J=2.1 Hz, 1H, H₂), 7.62 (d, J=9.0Hz, 1H, H₄), 8.01 (d, J=2.1 Hz, 1H, H₁), 8.26 (s, 1H, H₁₈).

¹³C NMR (75 MHz, MeOD): δ=24.9 (C₁₅), 28.3 (C₁₁), 29.7 (C₇), 29.9 (C₁₆),30.4 (C₁₀), 34.1 (C₁₃), 37.3 (C₁₄), 40.3 (C₆), 51.2 (C₁₇), 52.7 (MeO),115.5 (C_(11a) or C_(12a)), 117.0 (C_(11a) or C_(12a)), 124.7 (C₁),125.0 (C₂), 126.1 (C₄), 126.7 (C₈), 129.2 (C₁₈), 135.8 (C₃), 137.2 (C₉),140.2 (C_(4a) or C₁₂), 147.8 (C_(4a) or C₁₂), 150.2 (C₁₉), 158.8(C_(5a)), 162.3 (C₂₀).

MS (ESI+): m/z (%): 452.27 (100) [M+H]⁺, 454.27 (36).

IC₅₀ rh-AChE: 0.34±0.12 nM.

IC₅₀ rh-BuChE: 291±25 nM.

IC₅₀ erythrocyte h-AChE: 10.7 nM.

EXAMPLE 35{1-[4-(12-Amino-3-chloro-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinolin-9-yl)butyl]-1H-1,2,3-triazol-4-yl}methanolTrifluoroacetic Acid (HUP 34)

To a cooled (0° C.) stirred suspension of anhydrous LiAlH₄ (13.2 mg, 330mmol) in dry THF (0.5 mL) was added dropwise a solution of triazole (HUP33) (58 mg, 128 μmol) in dry THF (3.5 mL). The solution was stirred 20min (0° C. to r.t.) then quenched at 0° C. by the addition of water (100μL), then 5 M NaOH solution (100 μL), then water (300 μL). The reactionmixture was stirred 10 min at r.t. then concentrated to dryness andpurified by preparative HPLC (system B) to afford the desired Huprine(HUP 34) as a white solid (37 mg, 67%).

¹H NMR (300 MHz, MeOD): δ=1.26-1.33 (m, 2H, H₁₅), 1.58-1.72 (m, 2H,H₁₆), 1.90-2.02 (m, 4H, H₁₄, H₁₄, H₁₀, H₁₃), 2.05-2.10 (m, 1H, H₁₀),2.45 (dd, J=17.9 Hz, J=4.1 Hz, 1H, H₁₃), 2.78-2.81 (m, 1H, H₇), 2.86 (d,J=17.9 Hz, 1H, H₆), 3.20 (dd, J=17.7 Hz, J=5.5 Hz, 1H, H₆), 3.36-3.40(m, 1H, H₁₁), 4.23 (td, J=7.2 Hz, J=1.9 Hz, 2H, H₁₇), 4.66 (s, 2H, H₂O),5.59 (d, J=4.9 Hz, 1H, H₈), 7.57 (dd, J=9.2 Hz, J=2.1 Hz, 1H, H₂), 7.72(d, J=9.2 Hz, 1H, H₄), 7.79 (s, 1H, H₁₈), 8.34 (d, J=2.1 Hz, 1H, H₁)

¹³C NMR (75 MHz, MeOD): δ=25.0 (C₁₅), 27.5 (C₁₁), 28.1 (C₇), 29.3 (C₁₀),30.3 (C₁₆), 33.7 (C₁₃), 35.9 (C₆), 37.2 (C₁₄), 50.9 (C₁₇), 56.4 (C₂₀),115.3 (C_(11a) or C_(12a)), 115.4 (C_(11a) or C_(12a)), 119.2 (C₄),124.1 (C₁₈), 125.5 (C₈), 126.3 (C₁), 127.7 (C₂), 138.0 (C₃), 139.5 (C₉),140.4 (C_(4a) or C₁₂), 148.9 (C_(4a) or C₁₂), 153.0 (C₁₉), 156.7(C_(5a)).

MS (ESI+): m/z (%): 424.33 (100) [M+H]⁺, 426.27 (40).

IC₅₀ rh-AChE: 0.26±0.08 nM.

IC₅₀ rh-BuChE: 213±18 nM.

IC₅₀ erythrocyte h-AChE: 6.91 nM.

Exmaple 36{1-[4-(12-Amino-3-chloro-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinolin-9-yl)butyl]-1H-1,2,3-triazol-4-yl}methylTrifluoroacetate (HUP 35)

To a cooled (0° C.) stirred solution of the trifluoroacetate salt ofalcohol (HUP 34) (16 mg, 25.8 μmol) and trietylamine (14.7 μL, 105 μmol)in dry THF (1 mL) was added dropwise trifluoroacetic anhydride (8.7 μL,62.8 μmol). The solution was stirred 40 min at r.t. then concentrated todryness. The crude mixture was purified by flash chromatography(cyclohexane/AcOEt/MeOH 80/20/0 to 0/88/12, v/v/v, with 1% of Et₃N) toafford the desired Huprine (HUP 35) as a white solid (8.0 mg, 60%).

Rf (AcOEt/MeOH 8/2, v/v)=0.25.

¹H NMR (300 MHz, CDCl₃): δ=0.83-0.98 (m, 2H, H₁₅), 1.23-1.35 (m, 2H,H₁₆), 1.80-1.88 (m, 3H, H₁₀, H₁₀, H₁₃), 1.97-2.01 (m, 2H, H₁₄), 2.30(dd, J=17.5 Hz, J=5.1 Hz, 1H, H₁₃), 2.76-2.79 (m, 1H, H₇), 3.09 (d,J=16.4 Hz, 1H, H₆), 3.21 (dd, J=17.9 Hz, J=5.3 Hz, 1H, H₆), 3.41-3.44(m, 1H, H₁₁), 3.90 (t, J=7.0 Hz, 2H, H₁₇), 4.72 (d, J=3.8 Hz, 2H, H₂₀),5.56 (d, J=5.1 Hz, 1H, H₈), 7.12 (s, 1H, H₁₈), 7.39 (dd, J=9.0 Hz, J=1.9Hz, 1H, H₂), 7.78 (d, J=9.0 Hz, 1H, H₄), 7.96 (d, J=1.8 Hz, 1H, H₁).

¹³C NMR (75 MHz, CDCl₃): δ=23.1 (C₁₅), 27.6 (C₁₆), 28.2 (C₇), 28.4(C₁₄), 28.8 (C₁₁), 34.4 (C₁₃), 35.5 (C₁₀), 40.3 (C₆), 49.9 (C₁₇), 56.3(C₂₀), 115.5 (C_(11a) or C_(12a)), 117.0 (C_(11a) or C_(12a)), 122.4(C₁), 122.7 (?), 123.9 (C₁), 126.8 (C₈), 127.5 (C₂), 127.5 (C₄), 135.0(C₃), 135.4 (C₉), 147.3 (C_(4a) or C₁₂), 156.4 (C₁₉), 156.9 (C_(5a)).

¹⁹F NMR (282 MHz, CDCl₃): δ=−74.7.

MS (ESI+): m/z (%): 520.20 (100) [M+H]⁺, 522.33 (36).

IC₅₀ rh-AChE: 34.6±2.6 nM.

IC₅₀ rh-BuChE: 23% at 1 μM.

IC₅₀ erythrocyte h-AChE: 69.8 nM.

EXAMPLE 37 Ethyl4-(12-Amino-3-chloro-6-methylene-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinolin-9-yl)butanoate(HUP 36)

To a solution of diethylmalonate (HUP 27) (1.00 g, 2.2 mmol) in DMSO (10mL) and water (200 μL) was added lithium chloride (400 mg, 9.5 mmol).The suspension was refluxed for 17 h then cooled to r.t. and dilutedwith AcOEt (20 mL). The organic phase was washed with brine (40 mL),NaHCO₃ saturated solution (40 mL) and water (40 mL), dried with Na₂SO₄to give a brown solid. Purification by flash chromatography (AcOEt/MeOH10/0 to 9/1, v/v) afforded the desired Huprine (HUP 36) as a yellowsolid (295 mg, 34%).

Rf (AcOEt/MeOH 8/2, v/v)=0.88.

¹H NMR (300 MHz, CDCl₃): δ=1.16 (t, J=7.2 Hz, 3H, H₁₉), 1.53-1.59 (m,2H, H₁₅), 1.56 (t, J=7.5 Hz, 2H, H₁₄), 1.90-2.10 (m, 5H, H₁₆, H₁₆, H₁₀,H₁₀, H₁₃), 2.43 (dd, J=17.0 Hz, J=3.0 Hz, 1H, H₁₃), 3.18-3.21 (m, 1H,H₇), 3.26-3.30 (m, 1H, H₁₁), 3.99 (q, J=6.0 Hz, 2H, H₁₈), 4.81 (brs, 2H,NH₂), 5.19 (d, J=2.2 Hz, 1H, H₂O), 5.48 (d, J=5.3 Hz, 1H, H₈), 6.31 (d,J=2.1 Hz, 1H, H₂₀), 7.22 (dd, J=9.0 Hz, J=2.1 Hz, 1H, H₂), 7.56 (d,J=9.0 Hz, 1H, H₁), 7.89 (d, J=2.1 Hz, 1H, H₄).

¹³C NMR (75 MHz, CDCl₃): δ=14.2 (C₁₉), 22.5 (C₁₅), 28.2 (C₇), 29.7(C₁₆), 32.8 (C₁₀), 33.5 (C₁₃), 36.7 (C₁₄), 38.0 (C₁₁), 60.2 (C₁₈), 112.5(C₂₀), 114.9 (C_(11a) or C_(12a)), 116.4 (C_(11a) or C_(12a)), 121.5(C₁), 124.8 (2C, C₂, C₈), 128.6 (C₄), 134.2 (C₃), 134.8 (C₉), 146.0(C_(4a) or C₁₂), 146.6 (C_(4a) or C₁₂), 147.6 (C_(5a)), 157.3 (C₆),173.7 (C₁₇).

MS (ESI+): m/z (%): 397.32 (100) [M+H]⁺, 399.31 (35), 400.31 (9).

IC₅₀ rh-AChE: 90.6±8.4 nM.

IC₅₀ rh-BuChE: 11% at 1 μM.

EXAMPLE 384-(12-Amino-3-chloro-6-methylene-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinolin-9-yl)butan-1-ol Trifluoroacetic Acid (HUP 37)

To a cooled (0° C.) stirred suspension of anhydrous LiAlH₄ (30.4 mg, 760μmol) in dry THF (2 mL) was added dropwise a solution of ester (HUP 36)(151 mg, 380 μmol) in dry THF (5 mL). The solution was stirred 20 h (0°C. to r.t.) then quenched carefully at 0° C. by the addition of water(150 μL), then 5 M NaOH solution (150 μL), then water (450 μL). Thereaction mixture was stirred 10 min at r.t. then dried with Na₂SO₄. Thedried solution and washings (with AcOEt) were filtered and concentratedunder reduced pressure to give a yellow solid (276 mg). Purification bytwo successive flash chromatographies (AcOEt/MeOH 100/0 to 95/5, v/v)afforded a pale yellow solid (55 mg) still containing impurities.Purification by preparative HPLC (System B) afforded a pale orange solid(16.0 mg, 9%) containing the trifluoroacetate salt of the desiredHuprine (HUP 37) (70% in NMR) along with another inseparable isomer (30%in NMR).

Rf (free base, AcOEt/MeOH 9/1, v/v)=0.50.

¹H NMR (300 MHz, CDCl₃): δ=1.23-1.45 (m, 4H, H₁₄, H₁₅), 1.88-2.00 (m,2H, H₁₆), 2.06-2.19 (m, 3H, H₁₀, H₁₀, H₁₃), 2.57 (d, J=14.3 Hz, 1H,H₁₃), 3.30-3.49 (m, 6H, H₇, H₆, H₆, H₁₁, H₁₇, H₁₇), 5.54 (m, 1H, H₈),5.75 (d, J=2.3 Hz, 1H, H₁₈), 6.13 (d, J=2.3 Hz, 1H, H₁₈), 7.60 (dd,J=9.0 Hz, J=1.9 Hz, 1H, H₂), 8.01 (d, J=1.9 Hz, 1H, H₄), 8.36 (d, J=9.0Hz, 1H, H₁).

¹³C NMR (75 MHz, CDCl₃): δ=24.8 (C₁₅), 28.5 (C₇), 30.6 (C₁₄), 32.8(C₁₀), 33.4 (C₁₃), 37.9 (C₁₆), 38.9 (C₁₁), 62.5 (C₁₇), 115.4 (C_(11a) orC_(12a)), 115.6 (C_(11a) or C_(12a)), 117.3 (C₁₈), 119.8 (C₄), 123.7(C₈), 126.2 (C₁), 128.0 (C₂), 138.9 (C₃), 139.8 (C₉), 141.0 (C_(4a) orC₁₂), 142.9 (C_(4a) or C₁₂), 146.7 (C_(5a)), 157.4 (C₆).

IC₅₀ rh-AChE: 256±34 nM.

IC₅₀ rh-BuChE: 15% at 1 μM.

EXAMPLE 39{1-[4-(12-Amino-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinolin-9-yl)butyl]-1H-1,2,3-triazol-4-yl}methanolTrifluoroacetic Acid (HUP 38)

To a cooled (0° C.) stirred suspension of anhydrous LiAlH₄ (13.2 mg, 330μmol) in dry THF (0.5 mL) was added dropwise a solution of triazole (HUP33) (58 mg, 128 μmol) in dry THF (3.5 mL). The solution was stirred 20min (0° C. to r.t.) then quenched at 0° C. by the addition of water (100μL), then 5 M NaOH solution (100 μL), then water (300 μL). The reactionmixture was stirred 10 min at r.t. then concentrated to dryness andpurified by preparative HPLC (MeOH/TFA 0.1%) to afford the desiredHuprine (HUP 38) an off white solid (7.1 mg, 11%).

¹H NMR (300 MHz, MeOD): δ=1.26-1.34 (m, 2H, H₁₅), 1.59-1.72 (m, 2H,H₁₆), 1.91-2.12 (m, 5H, H₁₄, H₁₄, H₁₀, H₁₃, H₁₀), 2.46 (dd, J=17.7 Hz,J=4.3 Hz, 1H, H₁₃), 2.79-2.81 (m, 1H, H₇), 2.88 (d, J=17.9 Hz, 1H, H₆),3.21 (dd, J=17.9 Hz, J=5.3 Hz, 1H, H₆), 3.38-3.41 (m, 1H, H₁₁), 4.23(td, J=7.2 Hz, J=1.9 Hz, 2H, H₁₇), 4.66 (s, 2H, H₂₀), 5.59 (d, J=4.7 Hz,1H, H₈), 7.61 (td, J=8.1 Hz, J=0.9 Hz, 1H, H₂), 7.71 (d, J=8.3 Hz, 1H,H₄), 7.77 (s, 1H, H₁₈), 7.86 (td, J=8.3 Hz, J=1.1 Hz, 1H, H₁), 8.34 (d,J=8.5 Hz, 1H, H₁).

¹³C NMR (75 MHz, MeOD): δ=25.1 (C₁₅), 27.6 (C₁₁), 28.3 (C₇), 29.5 (C₁₀),30.4 (C₁₆), 33.9 (C₁₃), 35.9 (C₆), 37.3 (C₁₄), 51.0 (C₁₇), 56.4 (C₂₀),114.9 (C_(11a) or C_(12a)), 116.8 (C_(11a) or C_(12a)), 120.1 (C₄),124.1 (C₁₈), 124.2 (C₁), 125.6 (C₈), 127.2 (C₂), 134.5 (C₃), 138.1 (C₉),138.1 (C_(4a) or C₁₂), 138.9 (C_(4a) or C₁₂), 152.4 (C₁₉), 156.8(C_(5a)).

MS (ESI+): m/z (%): 390.27 (100) [M+H]⁺, 391.27 (28).

IC₅₀ rh-AChE: 94.1±2.8 nM.

IC₅₀ rh-BuChE: 357±16 nM.

EXAMPLE 402-(12-Amino-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinolin-9-yl)Ethyl Methanesulfonate (HUP 39)

To a cooled (0° C.) stirred solution of alcohol (HUP 2) (393 mg, 1 mmol)and triethylamine (140 μL, 1.5 mmol) in dry THF/dioxane mixture (90 mL,2/1, v/v) was added methane sulfonyl chloride (80 μL, 1.5 mmol) dropwiseover 5 min. The solution was stirred 1 h (0° C. to r.t.). The reactionmixture was concentrated almost to dryness under reduced pressure thenpoured onto a saturated aqueous solution of NaHCO₃. The aqueous phasewas extracted with AcOEt (3×25 mL). The combined organic layers weredried with Na₂SO₄ and concentrated under reduced pressure to afford ayellow solid. Purification by flash chromatography (petroleumether/AcOEt 3/7 then AcOEt then AcOEt/MeOH 9/1) afforded the desiredHuprine (HUP 39) as an off white solid (322 mg, 90%).

Rf (AcOEt/MeOH 8/2, v/v)=0.11.

¹H NMR (300 MHz, CDCl₃): δ=1.82-1.95 (m, 3H, H₁₀, H₁₀, H₁₃), 2.15 (t,J=6.4 Hz, 2H, H₁₄), 2.38 (dd, J=16.6 Hz, J=3.2 Hz, 1H, H₁₃), 2.54 (s,3H, OMs), 2.67-2.73 (m, 1H, H₇), 2.90 (d, J=17.3 Hz, 1H, H₆), 3.08 (dd,J=17.5 Hz, J=5.5 Hz, 1H, H₆), 3.14-3.19 (m, 1H, H₁₁), 4.01 (t, J=6.6 Hz,2H, H₁₅), 5.12 (brs, 2H, NH₂), 5.58 (d, J=5.3 Hz, 1H, H₈), 7.26 (t,J=7.5 Hz, 1H, H₂), 7.28 (td, J=7.0 Hz, J=0.7 Hz, 1H, H₃), 7.71-7.80 (m,2H, H₄, H₁).

¹³C NMR (75 MHz, CDCl₃): δ=27.2 (C₁₁), 28.3 (C₇), 28.9 (C₁₀), 33.7(C₁₃), 36.4 (C₁₄), 36.7 (OMs), 39.3 (C₆), 68.2 (C₁₅), 114.3 (C_(11a) orC_(12a)), 117.3 (C_(11a) or C_(12a)), 120.4 (C₁), 123.9 (C₂), 128.0(C₄), 128.4 (C₈), 128.8 (C₃), 131.2 (C₉), 146.3 (C_(4a) or C₁₂), 146.4(C_(4a) or C₁₂), 156.7 (C_(5a)).

MS (ESI+): m/z (%): 359.27 (100) [M+H]⁺, 360.20 (23).

IC₅₀ rh-AChE: 149±6 nM.

IC₅₀ rh-BuChE: 171±4 nM.

EXAMPLE 419-(2-Azidoethyl)-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinolin-12-amine(HUP 40)

A suspension of mesylate (HUP 39) (286 mg, 0.8 mmol) and sodium azide(208 mg, 3.2 mmol) in dry DMF (2.5 mL) was stirred under argon at 80° C.for 6 h30. The reaction mixture was then cooled to r.t. and water (5 mL)was added under stirring. Additional water (35 mL) and 30% aqueousNa₂CO₃ solution (10 mL) were added. Aqueous phase was extracted withAcOEt (3×30 mL) and the combined organic layers were dried with Na₂SO₄.Concentration under reduced pressure afforded a yellow oil. Purificationby flash chromatography (AcOEt/MeOH 100/0 to 95/5, v/v, thenAcOEt/EtOH/NEt₃ 90/9/1, v/v/v) afforded the desired Huprine (HUP 40) asa pale yellow solid (102 mg, 42%).

Rf (AcOEt/MeOH 8/2, v/v)=0.11.

¹H NMR (300 MHz, MeOD): δ=1.84-2.10 (m, 5H, H₁₀, H₁₀, H₁₃, H₁₄, H₁₄),2.46 (dd, J=17.7 Hz, J=4.7 Hz, 1H, H₁₃), 2.65-2.70 (m, 1H, H₇), 2.86 (d,J=17.5 Hz, 1H, H₆), 3.04 (dd, J=17.5 Hz, J=5.5 Hz, 1H, H₆), 3.07-3.16(m, 2H, H₁₅), 3.29-3.34 (m, 1H, H₁₁), 5.62 (d, J=5.5 Hz, 1H, H₈), 7.33(td, J=6.8 Hz, J=1.1 Hz, 1H, H₂), 7.54 (td, J=7.0 Hz, J=1.3 Hz, 1H, H₃),7.68 (dd, J=8.5 Hz, J=0.6 Hz, 1H, H₄), 8.05 (dd, J=8.5 Hz, J=0.7 Hz, 1H,H₁).

¹³C NMR (75 MHz, MeOD): δ=28.1 (C₁₁), 29.5 (C₇), 30.0 (C₁₀), 34.6 (C₁₃),37.7 (C₁₄), 39.2 (C₆), 50.3 (C₁₅), 114.8 (C_(11a) or C_(12a)), 118.3(C_(11a) or C_(12a)), 122.8 (C₁), 124.9 (C₂), 126.3 (C₄), 128.2 (C₈),130.5 (C₃), 134.8 (C₉), 146.0 (C_(4a) or C₁₂), 150.8 (C_(4a) or C₁₂),156.7 (C_(5a)).

MS (ESI+): m/z (%): 306.25 (100) [M+H]⁺, 307.11 (20).

EXAMPLE 429-(2-Aminoethyl)-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinolin-12-amineDihydrochloride (HUP 41)

A solution of azide (HUP 40) (100 mg, 327 μmol) and triphenylphosphine(86 mg, 327 μmol) in THF (1.6 mL) was stirred 30 min at 0° C. and 1 h(0° C. to r.t.). Water (16 μL) was then added at 0° C. and the mixturewas stirred at r.t. for 17 h. The reaction mixture was concentrated todryness then purified by preparative HPLC (System B) and concentratedunder reduced pressure to afford the ditrifluoroacetate salt of thedesired Huprine (HUP 41) as a white solid (72 mg, 43%). Theditrifluoroacetate salt was suspended in CHCl₃ (3 mL) then convertedinto free base by addition of ethanol/triethylamine 9/1, v/v solution (2mL). The solvents were removed and the salts precipitated inchloroform/acetone 3/2, v/v, filtered and washed with CHCl₃. Thesolvents were removed, then the residue was dissolved in MeOH (4 mL) andneutralized by addition of concentrated 37% aqueous HCl solution (2 mL).Evaporation of the solvents afforded the dihydrochloride of the desiredHuprine (HUP 41) as a pale grey solid (36 mg, 31%).

¹H NMR (300 MHz, MeOD): δ=1.93-2.16 (m, 3H, H₁₀, H₁₃, H₁₀), 2.23 (t,J=7.7 Hz, 2H, H₁₄), 2.60 (dd, J=17.7 Hz, J=3.6 Hz, 1H, H₁₃), 2.83-2.87(m, 1H, H₇), 2.88-2.97 (m, 3H, H₆, H₁₅, H₁₅), 3.21 (dd, J=18.1 Hz, J=5.5Hz, 1H, H₆), 3.41-3.45 (m, 1H, H₁₁), 5.74 (d, J=4.5 Hz, 1H, H₈), 7.57(t, J=7.3 Hz, 1H, H₂), 7.71 (d, J=7.9 Hz, 1H, H₄), 7.80 (td, J=7.0 Hz,J=0.9 Hz, 1H, H₃), 7.32 (d, J=8.5 Hz, 1H, H₁).

¹³C NMR (75 MHz, MeOD): δ=27.2 (C₁₁), 28.1 (C₇), 28.9 (C₁₀), 34.1 (C₁₃),35.4 (C₁₄), 35.8 (C₆), 38.7 (C₁₅), 114.4 (C_(11a) or C_(12a)), 116.7(C_(11a) or C_(12a)), 120.0 (C₄), 124.2 (C₁), 127.1 (C₂), 128.0 (C₈),134.1 (C₉), 134.3 (C₃), 138.9 (C_(4a) or C₁₂), 152.0 (C_(4a) or C₁₂),156.7 (C_(5a)).

MS (ESI+): m/z (%): 280.30 (100) [M+H]⁺, 281.23 (24), 140.59 (10)[M/2+H]²⁺.

EXAMPLE 43 Ethyl(3,12-dichloro-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinolin-9-yl)acetate(HUP 42)

A mixture of 3-ethylacetate-2-oxa-1-adamantyl methanesulfonate (318 mg,1.0 mmol), anhydrous aluminium trichloride (160 mg, 1.2 mmol) and 4 Åmolecular sieve in distilled 1,2-dichloroethane (3 mL) was stirred atreflux temperature for 1 h, then cooled to 30° C. To the reactionmixture was added slowly a solution of 4-chloro-2-aminobenzok acid (206mg, 1.2 mmol) in dioxane (5 mL). The white precipitate which formed wasstirred at r.t. for 15 min then the mixture was cooled to 0° C. andphosphorous oxychloride (1.86 mL) was added dropwise. The reactionmixture was stirred 5 h at r.t. then 15 h at 90° C. then hydrolyzd at 0°C. with slow addition of water (5 mL), THF (5 mL) and 5 M aqueous NaOHsolution (12 mL). After 30 min stirring at r.t., the salts were filteredand the residue washed with DCM. The filtrate was extracted with DCM(3×30 mL). The combined organic layers were dried with Na2SO4 andconcentrated under reduced pressure to afford a yellow oil. Purificationby flash chromatography (cyclohexane/AcOEt 10/0 to 8/2, v/v) affordedthe desired Huprine as a pale yellow solid (165 mg, 44%).

Rf (cyclohexane/AcOEt 7/3, v/v)=0.59.

IR (KBr): ν=2930, 1734, 1608, 1545, 1474, 1396, 1369, 1332, 1294, 1253,1153, 1074, 1033, 929, 770 cm-1.

¹H NMR (300 MHz, CDCl₃): δ=0.96 (t, J=7.1 Hz, 3H, H₁₈), 1.92-1.99 (m,1H, H₁₀), 2.07-2.14 (m, 1H, H₁₀), 2.19 (d, J=17.7 Hz, 1H, H₁₃), 2.66(dd, J=17.7 Hz, J=5.5 Hz, 1H, H₁₃), 2.74-2.88 (m, 2H, H7, H₁₄), 3.09(dt, J=17.7 Hz, J=1.9 Hz, 1H, H₆), 3.20 (dd, J=17.9 Hz, J=5.3 Hz, 1H,H₆), 3.74-3.78 (m, 1H, H₁₁), 3.92 (qd, J=7.1 Hz, J=2.3 Hz, 2H, H₁₇),5.69 (d, J=5.5 Hz, 1H, H₈), 7.44 (dd, J=9.0 Hz, J=1.9 Hz, 1H, H₂), 7.94(d, J=1.9 Hz, 1H, H₄), 8.07 (d, J=9.0 Hz, 1H, H₁).

¹³C NMR (75 MHz, CDCl₃): δ=14.0 (C₁₈), 28.4 (C₁₀), 28.5 (C₇), 30.6(C₁₁), 35.5 (C₁₃), 40.2 (C₆), 43.2 (C₁₄), 60.6 (C₁₇), 124.1 (C_(11a) orC_(12a)), 125.5 (C₁), 127.5 (C₂), 127.6 (C₄), 129.2 (C₈), 130.3 (C_(11a)or C_(12a)), 133.2 (C₉), 135.4 (C₃), 141.0 (C_(4a) or C₁₂), 147.5(C_(4a) or C₁₂), 159.9 (C_(5a)), 171.3 (C₁₅).

MS (ESI+): m/z (%): 376.33 (100) [M+H]⁺, 378.20 (67), 380.27 (15).

EXAMPLE 443-Chloro-9-(4-{4-[(6,7-dimethoxy-1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)methyl]-1H-1,2,3-triazol-1-yl}butyl)-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinolin-12-amineDitrifluoroacetic Acid (HUP32-PIQ1)

A mixture of azide (HUP 32) (6.2 mg, 16.3 μmol),2-Prop-2-yn-1-yl-6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline(PIQ 1) (5.1 mg, 16.3 μmol) and copper iodide (2.5 mg, 13.0 μmol) inMeCN (0.5 mL) was stirred at r.t. with light protection for 10 days. Thereaction mixture was concentrated to dryness then purified bypreparative HPLC (system B) to afford the desired Huprine (HUP32-PIQ1)as a white solid (10.9 mg, 74%).

¹H NMR (300 MHz, MeOD): δ=1.25-1.33 (m, 2H, H₁₅), 1.59-1.75 (m, 2H,H₁₆), 1.93-2.10 (m, 5H, H₁₄, H₁₄, H₁₀, H₁₃, H₁₀), 2.49 (dd, J=17.7 Hz,J=3.9 Hz, 1H, H₁₃), 2.78-2.81 (m, 1H, H₇), 2.86 (d, J=19.7 Hz, 1H, H₆),3.20 (dd, J=17.7 Hz, J=5.5 Hz, 1H, H₆), 3.20-3.45 (m, 3H, H₂₂, H₂₂,H₁₁), 3.53-3.70 (m, 4H, H₂₀, H₂₀, H₂₁, H₂₁), 3.61 (s, 3H, OMe), 3.87 (s,3H, OMe), 4.26-4.33 (m, 2H, H₁₇), 5.61 (d, J=4.3 Hz, 1H, H₈), 5.85 (s,1H, H₂₇), 6.36 (s, 1H, H₂₆), 6.92 (s, 1H, H₂₃), 7.37-7.40 (m, 2H, H₂₉,H₃₃), 7.49-7.52 (m, 3H, H₃₀, H₃₁, H₃₂), 7.57 (dd, J=9.0 Hz, J=1.7 Hz,1H, H₂), 7.73 (d, J=1.7 Hz, 1H, H₄), 8.09 (s, 1H, H₁₈), 8.34 (d, J=9.0Hz, 1H, H₁).

¹³C NMR (75 MHz, MeOD): δ=25.1 (C₁₅), 27.5 (C₁₁), 28.1 (C₇), 29.3 (C₁₀),30.4 (C₁₆), 30.7 (C₂₂), 33.8 (C₁₃), 35.9 (C₆), 37.2 (C₁₄), 48.5 (C₂₁),51.2 (C₁₇), 52.3 (C₂₀), 56.4 (MeO), 56.5 (MeO), 67.2 (C₂₇), 112.3 (2C,C₂₃, C₂₆), 115.3 (C_(11a) or C_(12a)), 115.4 (C_(11a) or C_(12a)), 119.3(C₄), 123.3 (C_(26a)), 124.0 (C_(22a)), 124.8 (C₁₈), 125.5 (C₈), 126.3(C₁), 127.7 (C₂), 130.5 (3C, C₃₀, C₃₁, C₃₂), 131.4 (2C, C₂₉, C₃₃), 131.1(C₂₈), 138.0 (C₃), 139.5 (C₉), 140.4 (C_(4a) or C₁₂), 150.1 (C_(4a) orC₁₂), 151.2 (2C, C₂₄, C₂₅), 153.0 (C₁₉), 156.7 (C_(5a)).

MS (ESI+): m/z (%): 675.40 (100) [M+H]⁺, 338.27 (85) [M/2+H]²⁺, 677.33(65).

IC₅₀ rh-AChE: 3.31±0.2 nM.

IC₅₀ rh-BuChE: 20.6±0.2 nM.

EXAMPLE 453-Chloro-9-(4-{4-[2-(6,7-dimethoxy-1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)ethyl]-1H-1,2,3-triazol-1-yl}butyl)-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinolin-12-amineDitrifluoroacetic Acid (HUP32-PIQ2)

A mixture of azide (HUP 32) (19.0 mg, 51.6 μmol),2-But-3-yn-1-yl-6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline(PIQ 2) (20.1 mg, 62.5 μmol) and copper iodide (2.0 mg, 10.5 μmol) inMeCN (1 mL) was stirred at r.t. with light protection for 24 h. Thereaction mixture was concentrated to dryness then purified bypreparative HPLC (system B) to afford the desired Huprine (HUP32-PIQ2)as a light yellow solid (31.1 mg, 66%).

¹H NMR (300 MHz, MeOD): δ=1.25-1.35 (m, 2H, H₁₅), 1.59-1.73 (m, 2H,H₁₆), 1.91-2.10 (m, 5H, H₁₄, H₁₄, H₁₀, H₁₃, H₁₀), 2.48 (dd, J=17.1 Hz,J=3.4 Hz, 1H, H₁₃), 2.78-2.81 (m, 1H, H₇), 2.87 (d, J=18.1 Hz, 1H, H₆),3.21 (dd, J=17.9 Hz, J=5.5 Hz, 1H, H₆), 3.23-3.36 (m, 6H, H₂₀, H₂₁,H₂₂), 3.37-3.40 (m, 1H, H₁₁), 3.50-3.68 (m, 2H, H₂₂), 3.62 (s, 3H, OMe),3.87 (s, 3H, OMe), 4.21 (t, J=6.8 Hz, 2H, H₁₇), 5.58 (d, J=4.7 Hz, 1H,H₈), 5.87 (s, 1H, H₂₈), 6.39 (s, 1H, H₂₇), 6.93 (s, 1H, H₂₄), 7.35-7.39(m, 2H, H₃₀, H₃₄), 7.46-7.51 (m, 3H, H₃₁, H₃₂, H₃₃), 7.56 (dd, J=9.0 Hz,J=1.9 Hz, 1H, H₂), 7.73 (d, J=1.9 Hz, 1H, H₄), 7.78 (s, 1H, H₁₈), 8.34(d, J=9.0 Hz, 1H, H₁).

¹³C NMR (75 MHz, MeOD): δ=21.6 (C₂₀), 24.2 (C₂₃), 25.0 (C₁₅), 27.5(C₁₁), 28.1 (C₇), 29.3 (C₁₀), 30.4 (C₁₆), 33.9 (C₁₃), 35.9 (C₆), 37.2(C₁₄), 45.9 (C₂₂), 51.0 (C₁₇), 53.5 (C₂₁), 56.4 (MeO), 56.5 (MeO), 67.5(C₂₈), 112.3 (2C, C₂₄, C₂₇), 115.3 (C_(11a) or C_(12a)), 115.4 (C_(11a)or C_(12a)), 119.2 (C₄), 122.9 (C_(27a)), 124.2 (C_(23a)), 124.7 (C₁₈),125.4 (C₈), 126.3 (C₁), 127.7 (C₂), 130.4 (3C, C₃₁, C₃₂, C₃₃), 131.4(2C, C₃₀, C₃₄), 131.9 (C₂₉), 138.0 (C₃), 139.5 (C₉), 140.4 (C_(4a) orC₁₂), 150.1 (C_(4a) or C₁₂), 151.2 (2C, C₂₅, C₂₆), 153.0 (C₁₉), 156.7(C_(5a)).

MS (ESI+): m/z (%): 689.27 (100) [M+H]⁺, 345.13 (37) [M/2+H]²⁺.

IC₅₀ rh-AChE: 0.64±0.4 nM.

IC₅₀ rh-BuChE: 14.1±0.1 nM.

EXAMPLE 463-Chloro-9-(4-{4-[3-(6,7-dimethoxy-1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)propyl]-1H-1,2,3-triazol-1-yl}butyl)-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinolin-12-amineDitrifluoroacetic Acid (HUP32-PIQ3)

A mixture of azide (HUP 32) (19.0 mg, 51.6 μmol),2-Pent-4-yn-1-yl-6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline(PIQ 3) (20.1 mg, 60.0 μmol) and copper iodide (2.0 mg, 10.5 μmol) inMeCN (1 mL) was stirred at r.t. with light protection for 24 h. Thereaction mixture was concentrated to dryness then purified bypreparative HPLC (system B) to afford the desired Huprine (HUP32-PIQ3)as a white solid (35.3 mg, 74%).

¹H NMR (300 MHz, MeOD): δ=1.25-1.36 (m, 2H, H₁₅), 1.57-1.74 (m, 2H,H₁₆), 1.90-2.10 (m, 5H, H₁₄, H₁₄, H₁₀, H₁₃, H₁₀), 2.10-2.30 (m, 2H,H₂₁), 2.49 (dd, J=18.0 Hz, J=4.1 Hz, 1H, H₁₃), 2.68-2.78 (m, 2H, H₂₀),2.78-2.82 (m, 1H, H₇), 2.87 (d, J=18.0 Hz, 1H, H₆), 3.21 (dd, J=17.9 Hz,J=5.3 Hz, 1H, H₆), 3.18-3.35 (m, 4H, H₂₂, H₂₄), 3.38-3.41 (m, 1H, H₁₁),3.50-3.68 (m, 2H, H₂₃), 3.59 (s, 3H, OMe), 3.85 (s, 3H, OMe), 4.20 (t,J=7.0 Hz, 2H, H₁₇), 5.59 (d, J=4.9 Hz, 1H, H₈), 5.74 (s, 1H, H₂₉), 6.31(s, 1H, H₂₈), 6.90 (s, 1H, H₂₅), 7.29-7.33 (m, 2H, H₃₁, H₃₅), 7.43-7.47(m, 3H, H₃₂, H₃₃, H₃₄), 7.56 (dd, J=9.0 Hz, J=1.9 Hz, 1H, H₂), 7.71 (s,1H, H₁₈), 7.73 (d, J=1.9 Hz, 1H, H₄), 8.34 (d, J=9.0 Hz, 1H, H₁).

¹³C NMR (75 MHz, MeOD): δ=23.3 (C₂₀), 24.2 (C₂₄), 24.7 (C₂₁), 25.1(C₁₅), 27.5 (C₁₁), 28.1 (C₇), 29.3 (C₁₀), 30.4 (C₁₆), 33.9 (C₁₃), 35.9(C₆), 37.2 (C₁₄), 46.1 (C₂₃), 51.0 (C₁₇), 53.6 (C₂₂), 56.3 (MeO), 56.4(MeO), 67.9 (C₂₉), 112.3 (C₂₅), 112.4 (C₂₈), 115.3 (C_(11a) or C_(12a)),115.4 (C_(11a) or C_(12a)), 119.2 (C₄), 123.1 (C_(28a)), 124.7(C_(24a)), 124.8 (C₁₈), 125.4 (C₈), 126.3 (C₁), 127.7 (C₂), 130.4 (3C,C₃₂, C₃₃, C₃₄), 131.3 (2C, C₃₁, C₃₅), 131.6 (C₃₀), 138.0 (C₃), 139.5(C₉), 140.4 (C_(4a) or C₁₂), 150.0 (C_(4a) or C₁₂), 151.1 (2C, C₂₆,C₂₇), 153.0 (C₁₉), 156.7 (C_(5a)).

MS (ESI+): m/z (%): 352.40 (100) [M/2+H]²⁺, 703.27 (28) [M+H]⁺.

IC₅₀ rh-AChE: 0.61±0.1 nM.

IC₅₀ rh-BuChE: 11.4±0.6 nM.

EXAMPLE 473-Chloro-9-(4-{4-[4-(6,7-dimethoxy-1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)butyl]-1H-1,2,3-triazol-1-yl}butyl)-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinolin-12-amineDitrifluoroacetic Acid (HUP32-PIQ4)

A mixture of azide (HUP 32) (30.6 mg, 58.0 μmol),2-Hex-5-yn-1-yl-6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline(PIQ 4) (24.8 mg, 72.0 μmol) and copper iodide (3.6 mg, 19.0 μmol) inMeCN (1.2 mL) and MeOH (0.3 mL) was stirred at r.t. with lightprotection for 16 h. The reaction mixture was concentrated to drynessthen purified by preparative HPLC (system B) to afford the desiredHuprine (HUP32-PIQ4) as a white solid (21.5 mg, 32%).

¹H NMR (300 MHz, MeOD): δ=1.28-1.35 (m, 4H, H₁₅, H₂₂), 1.60-1.70 (m, 4H,H₁₆, H₂₁), 1.84-2.00 (m, 5H, H₁₄, H₁₄, H₁₀, H₂₅, H₂₅), 2.00-2.10 (m, 2H,H₁₃, H₁₀), 2.48 (dd, J=17.5 Hz, J=3.9 Hz, 1H, H₁₃), 2.65-2.75 (m, 2H,H₂₀), 2.78-2.82 (m, 1H, H₇), 2.87 (d, J=17.7 Hz, 1H, H₆), 3.21 (dd,J=17.7 Hz, J=5.5 Hz, 1H, H₆), 3.18-3.31 (m, 4H, H₂₃, H₂₅), 3.38-3.41 (m,1H, H₁₁), 3.45-3.65 (m, 2H, H₂₄), 3.60 (s, 3H, OMe), 3.86 (s, 3H, OMe),4.20 (t, J=6.8 Hz, 2H, H₁₇), 5.59 (d, J=5.1 Hz, 1H, H₈), 5.74 (s, 1H,H₃₀), 6.33 (s, 1H, H₂₉), 6.91 (s, 1H, H₂₆), 7.32-7.36 (m, 2H, H₃₂, H₃₆),7.47-7.50 (m, 3H, H₃₃, H₃₄, H₃₅), 7.57 (dd, J=9.0 Hz, J=1.9 Hz, 1H, H₂),7.71 (s, 1H, H₁₈), 7.72 (d, J=1.9 Hz, 1H, H₄), 8.34 (d, J=9.0 Hz, 1H,H₁).

¹³C NMR (75 MHz, MeOD): δ=24.7 (C₂₅), 25.1 (C₁₅), 25.5 (C₂₀), 27.3(C₂₁), 27.5 (C₁₁), 28.1 (C₇), 29.3 (C₁₀), 30.4 (C₁₆), 22.8 (C₂₂), 33.8(C₁₃), 35.9 (C₆), 37.2 (C₁₄), 49.1 (C₂₄), 51.0 (C₁₇), 54.0 (C₂₃), 56.4(MeO), 56.5 (MeO), 67.9 (C₃₀), 112.3 (2C, C₂₅, C₂₈), 115.3 (C_(11a) orC_(12a)), 115.4 (C_(11a) or C_(12a)), 119.2 (C₄), 129. (C_(29a)), 124.8(C_(25a)), 124.9 (C₁₈), 125.5 (C₈), 126.3 (C₁), 127.7 (C₂), 130.4 (3C,C₃₃, C₃₄, C₃₅), 131.3 (2C, C₃₂, C₃₆), 131.6 (C₃₁), 138.0 (C₃), 139.5(C₉), 140.4 (C_(4a) or C₁₂), 150.0 (C_(4a) or C₁₂), 151.1 (2C, C₂₇,C₂₈), 153.0 (C₁₉), 156.7 (C_(5a)).

MS (ESI+): m/z (%): 359.33 (100) [M/2+H]²⁺, 717.40 (28) [M+H]⁺.

IC₅₀ rh-AChE: 0.78±0.1 nM.

IC₅₀ rh-BuChE: 9.5±0.6 nM.

EXAMPLE 484-{4-[4-(7-(dimethylamino)-2-oxo-2H-chromen-4-yl)butyl]-1H-1,2,3-triazol-1-yl}prop-2-yn-1-yl)-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinolin-12-amine Ditrifluoroacetic Acid (HUP32-COU1)

A mixture of azide (HUP32) (21.4 mg, 58 μmol),Prop-2-yn-1-yl[7-(dimethylamino)-2-oxo-2H-chromen-4-yl]acetate (COU1)(free base, 20.0 mg, 70 μmol) and copper iodide (4.4 mg, 23 μmol) inacetonitrile (1 mL) was stirred at r.t. with light protection for 24 h.The reaction mixture was concentrated to dryness then purified bypreparative HPLC (system A) to afford the desired huprine (HUP32-COU1)as fluorescent yellow solid (42.7 mg, 64%).

¹H NMR (300 MHz, MeOD): δ=1.15-1.34 (m, 2H, H₁₅), 1.52-1.68 (m, 2H,H₁₆), 1.86-2.0 (m, 5H, H₁₄, H₁₄, H₁₀, H₁₃, H₁₀), 2.42 (dd, J=17.2 Hz,J=3.6 Hz, 1H, H₁₃), 2.78-2.82 (m, 1H, H₇), 2.85 (d, J=18.0 Hz, 1H, H₆),3.03 (s, 6H, H₃₁, H₃₂), 3.19 (dd, J=17.9 Hz, J=5.1 Hz, 1H, H₆), 3.33 (m,1H, H₁₁), 3.81 (s, 2H, H₂₂), 4.22 (t, J=6.8 Hz, 2H, H₁₇), 5.22 (s, 2H,H₂₀), 5.55 (d, J=4.7 Hz, 1H, H₈), 5.97 (s, 1H, H₂₄), 6.46 (d, J=2.5 Hz,1H, H₂₇), 6.61 (dd, J=9.0 Hz, J=2.5 Hz, 1H, H₂₉), 7.36 (d, J=9.0 Hz, 1H,H₃₀), 7.54 (dd, J=9.0 Hz, J=1.9 Hz, 1H, H₂), 7.68 (d, J=1.9 Hz, 1H, H₄),7.81 (s, 1H, H₁₈), 8.31 (d, J=9.0 Hz, 1H, H₁).

¹³C NMR (75 MHz, MeOD): δ=25.0 (C₁₅), 27.5 (C₁₁), 28.1 (C₇), 29.3 (C₁₀),30.2 (C₁₆), 33.8 (C₁₃), 35.9 (C₆), 37.1 (C₁₄), 38.3 (C₂₂), 40.2 (2C,C₃₀, C₃₁), 50.9 (C₁₇), 59.0 (C₂₀), 98.7 (C₂₇), 109.5 (C_(12a)), 110.5(2C, C₂₄, C₂₉), 115.2 (C_(11a) or C_(30a)), 115.3 (C_(11a) or C_(30a)),119.2 (C₄), 125.5 (C₈), 125.9 (C_(26a) or C₁₂ or C₁₉), 126.3 (C₁), 126.8(C₃₀), 127.7 (C₂), 134.0 (C₃), 139.4 (C₉), 140.4 (C_(4a)), 151.4 (C₁₃),153.0 (C₂₈), 154.7 (C_(26a) or C₁₂ or C₁₉), 157.0 (C_(26a) or C₁₂ orC₁₉), 157.1 (C_(5a)), 164.0 (C₂₅), 170.6 (C₂₁).

MS (ESI+): m/z (%): 655.27 (32), 653.27 (100) [M+H]⁺

HPLC: tr=21.4 (purity >95%).

EXAMPLE 49 Preparation of HUP32-COU2

A mixture of azide (HUP32) (15.0 mg, 40.8 μmol),Prop-2-yn-1-yl[7-(dimethylamino)-2-oxo-2H-chromen-4-yl]amide (COU2)(free base, 14.0 mg, 49.0 μmol) and copper iodide (1.9 mg, 10 μmol) inactetonitrile (0.5 mL) was stirred at r.t. with light protection for 48h. The reaction mixture was concentrated to dryness then purified bypreparative HPLC (system A) to afford the desired Huprine (HUP32-COU2)as fluorescent yellow solid (9.6 mg, 31%).

¹H NMR (300 MHz, MeOD): δ=1.16-1.37 (m, 2H, H₁₅), 1.53-1.65 (m, 2H,H₁₆), 1.85-2.01 (m, 4H, H₁₄, H₁₄, H₁₀, H₁₀), 2.01-2.07 (m, 1H, H₁₃),2.34 (dd, J=17.2 Hz, J=3.6 Hz, 1H, H₁₃), 2.78-2.82 (m, 1H, H₇), 2.85 (d,J=18.0 Hz, 1H, H₆), 3.07 (s, 6H, H₃₁, H₃₂), 3.17 (dd, J=17.9 Hz, J=5.1Hz, 1H, H₆), 3.31 (m, 1H, H₁₁), 3.72 (s, 2H, H₂₂), 4.19 (t, J=6.8 Hz,2H, H₁₇), 4.26 (s, 2H, H₂₀), 5.53 (d, J=4.7 Hz, 1H, H₈), 6.01 (s, 1H,H₂₄), 6.49 (d, J=2.5 Hz, 1H, H₂₇), 6.67 (dd, J=9.0 Hz, J=2.5 Hz, 1H,H₂₉), 7.48 (d, J=9.0 Hz, 1H, H₃₀), 7.55 (dd, J=9.0 Hz, J=1.9 Hz, 1H,H₂), 7.62 (s, 1H, H₁₈), 7.68 (d, J=1.9 Hz, 1H, H₄), 8.31 (d, J=9.0 Hz,1H, H₁).

¹³C NMR (75 MHz, MeOD): δ=24.8 (C₁₅), 27.4 (C₁₁), 28.1 (C₇), 29.3 (C₁₀),30.1 (C₁₆), 33.6 (C₁₃), 35.9 (C₆), 37.1 (C₁₄), 39.9 (C₂₂), 40.2 (2C,C₃₁, C₃₂), 50.8 (C₁₇), 59.8 (C₂₀), 98.7 (C₂₇), 109.7 (C_(12a)), 110.4(2C, C₂₄, C₂₉), 115.2 (C_(11a) or C_(30a)), 115.3 (C_(11a) or C_(30a)),119.2 (C₄), 123.9 (C_(26a) or C₁₂ or C₁₉), 125.5 (C₈), 126.3 (C₁), 126.9(C₃₀), 127.7 (C₂), 137.9 (C₃), 139.4 (C₉), 140.4 (C_(4a)), 152.7 (C₁₃ orC₂₈), 152.9 (C₁₃ or C₂₈), 154.7 (C_(26a) or C₁₂ or C₁₉), 156.7 (C_(26a)or C₁₂ or C₁₉), 157.1 (C_(5a)), 164.1 (C₂₅), 171.2 (C₂₁).

MS (ESI+): m/z (%): 652.33 (100) [M+H]⁺.

EXAMPLE 50 Preparation of HUP32-IND1

A mixture of azide (HUP32) (21.4 mg, 58.2 μmol),1-(Prop-2-ynyl)-1H-indole(IND1) (15.5 mg, 100 μmol) and copper iodide(6.0 mg, 31 μmol) in actetonitrile (1 mL) was stirred at r.t. with lightprotection for 24 h. The reaction mixture was concentrated to drynessthen purified by preparative HPLC (system A) to afford the desiredhuprine (HUP32-IND1) as a light red solid (30.7 mg, 61%).

MS (ESI+): m/z (%): 262.13 (28) [M/2+H]²⁺, 523.24 (100) [M+H]⁺.

HPLC: tr=23.5 (purity >95%).

EXAMPLE 51 Preparation of HUP32-IND2

A mixture of azide (HUP32) (21.4 mg, 58.2 μmol),1-(But-3-ynyl)-1H-indole (IND2) (16.9 mg, 100 μmol) and copper iodide(6.0 mg, 31 μmol) in actetonitrile (1 mL) was stirred at r.t. with lightprotection for 24 h. The reaction mixture was concentrated to drynessthen purified by preparative HPLC (system A) to afford the desiredhuprine (HUP32-IND2) as a light red solid (4.3 mg, 5%).

MS (ESI+): m/z (%): 269.40 (100) [M/2+H]²⁺, 539.26 (24) [M+H]⁺.

HPLC: tr=23.8 (purity 86%).

EXAMPLE 52 Preparation of HUP32-TPI1

A mixture of azide (HUP32) (21.4 mg, 58.2 μmol),2,3,4,9-Tetrahydro-2-(prop-2-ynyl)-1H-pyrido[3,4-b]indole (TPI1) (21.0mg, 100 μmol) and copper iodide (6.0 mg, 31 μmol) in actetonitrile (1mL) was stirred at r.t. with light protection for 24 h. The reactionmixture was concentrated to dryness then purified by preparative HPLC(system A) to afford the desired huprine (HUP32-TPI1) as a white solid(34.2 mg, 64%).

MS (ESI+): m/z (%): 289.60 (100) [M/2+H]²⁺, 578.29 (28) [M+H]⁺.

HPLC: tr=18.5 (purity >95%).

EXAMPLE 53 Effect of HUP-COUA1 on Amyloid-bata Peptide

HUP32-COU1 effect on amyloid-beta peptide aggregation is drastic, allthe more in the presence of AChE. The measuring of thioflavin Tfluorescence allowed monitoring amyloid-beta peptide aggregation overtime, at various concentrations of HUP32-COU1 (330 pM to 67 nM), with orwithout AChE (experiments performed at 25 μM Aβ±1 μM AChE). Thioflavin Tfluorescence reveals not only the formation of fibrils, but also that ofother beta-sheets pleated, amyloid-beta peptide oligomers. The resultsshow that HUP32-COU1 interacts with amyloid-beta peptide even in theabsence of AChE, reducing amyloid-species formation; this is evidencedby a concentration-dependant increase in the lag-time before the onsetof ThT fluorescence. The results moreover suggest that HUP32-COU1 isable to breakdown amyloid-species, as evidenced by aconcentration-dependent decrease in the lag-time before the drop in ThTfluorescence. The concentrations at which these effects are at theirhalf-maxima were estimated to 180 and 50 nM, respectively, in theframework of a first-order inhibition model. In the presence of AChE,amyloid-species formation comparatively appears anecdotical, assuggested by the 10-fold decrease in ThT average fluorescence. Thecomplex formed by AChE and HUP32-COU1 displays an apparentnegative-effect on amyloid-species formation, which reaches its halfmaximum at 8 mM HUP32-COU1.

In summary, our results put forward HUP32-COU1 as a potent inhibitor ofamyloid-beta peptide and amyloid-beta peptide+AChE aggregation (intooligomers and/or fibrils) and as an amyloid-beta peptide/fibrilsbreaker. Moreover, they strongly suggest that the AChE-HUP32-COU1complex is an inhibitor of amyloid-beta peptide amyloid-speciesformation.

EXAMPLE 54 Preparation of an Affinity Resin

Coupling Method

The ligand (HUP 24; di-TFA salt; 50 mg; 90 μmoles) was dissolved inH₂O/15% MeOH, at pH 5.0 was contacted with ECH-Sepharose 4B resin(GE-Healthcare; 6 ml, 90 μmoles of active sites) with a ratioligand/active group of 1. The coupling was catalysed with an excess ofcarbodiimide (0.1 M final). Then, the resin was thoroughly rinced withwater buffered with 20 mM Tris, 200 mM NaCl, pH 7.4 and placed in acolumn.

Purification

The BuChE partially purified (containing albumin) in a buffer 20 mMTris, 200 mM NaCl, pH 7.4 is passed through the column. The main part ofthe active BuChE is retained in the column contrary to the main part ofthe proteic fraction (albumin). Further more stringent washing with 20mM Tris, 500 mM NaCl, pH 7.4 allow removing the remaining albumin.Elution is completed with a buffer 20 mM Tris pH 7.4, 1M NaCl,Tetramethylammonium 0.5 M, Decamethonium 1 mM. 95% pure BuChE isobtained, with a recovery of >90% of the introduced BuChE (verified bystandard Elmann based colorimetric assay).

The invention claimed is:
 1. A compound of formula I:

wherein, R is a moiety of formula -A-Y—Z, wherein, A is C₁-C₄ alkylene;Y is a single bond, —O—, —C(O)—, —C(O)O—, —OC(O)—, —OS(O)₂—, —NH—,—N(R⁴)— or

Z is H, halo, cyano, hydroxyl, azide, hydrazinyl, —OR⁵, —C(O)OR⁶,—NR⁶R⁷, —N⁺R⁶R⁷R⁸, —CH(COOR⁶)₂, —CH(CH₂OH)₂, CH₂—OC(O)—R⁹, C₁-C₄ alkyl,C₁-C₄ alkyl substituted with halogen or hydroxyl, C₂-C₄ alkenyl or C₂-C₄alkenyl substituted with halogen or hydroxyl; R⁴ and R⁵ are C₁-C₄ alkylor C₁-C₄ alkyloxycarbonyl; R⁶, R⁷ and R⁸ are independently H or C₁-C₄alkyl; and R⁹ is C₁-C₄ alkyl or C₁-C₄ alkyl substituted with halogen;with the proviso that R is not alkyl; R^(a), R^(b), R^(c) and R^(d) areindependently H, halogen, cyano, carboxyl, —O(C₁-C₄ alkyl), —S(C₁-C₄alkyl), or —CH₂S(C₁-C₄ alkyl); R¹ is H or ═CH₂; and R² is Cl or NR³R′³wherein R³ and R′³ are independently H, acetyl, C₁-C₄ alkyl, or—CO(C₁-C₄ alkyl); and pharmaceutically acceptable salts thereof.
 2. Thecompound of claim 1, wherein R is selected from the group consisting of:—CH₂—COO—C₂H₅, —(CH₂)₂—OH, —(CH₂)₂—OCO—CH₃, —(CH₂)₂—OCO—CF₃,—(CH₂)₂—O—CH₃, —(CH₂)₂—I, —(CH₂)₂—CN, —(CH₂)₂—Cl, —(CH₂)₂—F, —CH₂—COOH,—(CH₂)₂—N₃, —(CH₂)₂—OSO₂—CH₃, —(CH₂)₂—NH—NH₂, —(CH₂)₂—NH—OH,—(CH₂)₂—N(boc)-O(boc), —(CH₂)₂—OCO—NH₂, —(CH₂)₂—OCO—CH═CH₂,—CH₂—CO—N(CH₃)₂, —CH₂—CONH₂, —(CH₂)₂—N⁺H(CH3)₂, —(CH₂)₂—(C₂H₂N₃)—COOCH₃,—(CH₂)₂—(C₂H₂N3)—CH₂OH, —(CH₂)₂—N⁺H₃, —(CH₂)₂—N⁺(CH₃)₃,—(CH₂)₂—CH—(COOCH₃)₂, —(CH₂)₂—CH—(COOC₂H₅)₂, —(CH₂)₂—CH—(CH₂OH)₂,—(CH₂)₃—COO—CH3, —(CH₂)₄—OH, —(CH₂)₄—OSO₂—CH₃, —(CH₂)₄—N₃,—(CH₂)₄—(C₂H₂N₃)—COOCH₃, —(CH₂)₄—(C₂H₂N₃)—CH₂OH,—(CH₂)₄—(C₂H₂N₃)—CH₂OCOCF₃, —(CH₂)₃—COO—C₂H₅.
 3. The compound accordingto claim 1, wherein R² is NR³R′³.
 4. The compound according to claim 1,wherein R^(a), R^(b), R^(d) and R^(c) are H or R^(a), R^(b) and R^(d)are H and R^(c) is Cl.
 5. The compound according to claim 1, wherein R¹is H.
 6. The compound according to claim 1 selected from the groupconsisting of:

and pharmaceutically acceptable salts thereof.
 7. A compound selectedfrom the group consisting of:


8. A method of producing the compound according to claim 1 wherein saidmethod comprises the steps of: a) contacting the diketone of formula 1

with an α-haloester, to obtain the compound of formula 2

wherein R′ is a C₁-C₄ alkyl; b) transforming the alcoholic group of thecompound of formula 2 into a leaving group to obtain the compound offormula 3

wherein R″ is a leaving group; b′) eventually converting the compound offormula 3 into the compound of formula 4

c) contacting the compound of formula 3 or 4 with the compound offormula 5

wherein R^(a), R^(b), R^(c) and R^(d) are as defined in formula I, andR^(e) is CN or COOH, to obtain the compound of formula HUP

wherein R′ is a C₁-C₄ alkyl and R¹⁰ is NH₂ or Cl.
 9. A pharmaceuticalcomposition comprising a compound according claim
 1. 10. A resin foraffinity chromatography comprising the compound according to claim 1.11. An enantioselective catalyst, comprising the compound according toclaim 1.